Imatinib - Revision history

http://52.214.119.220/wiki/index.php?action=history&feed=atom&title=Imatinib Imatinib - Revision history 2026-04-08T15:58:18Z Revision history for this page on the wiki MediaWiki 1.11.2 http://52.214.119.220/wiki/index.php?title=Imatinib&diff=3118229&oldid=prev Alexander Berchansky at 08:25, 28 November 2019 2019-11-28T08:25:58Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 08:25, 28 November 2019</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 8:</td> <td colspan="2" class="diff-lineno">Line 8:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>* 2009 Global Sales: $3.9 Billion</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>* 2009 Global Sales: $3.9 Billion</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>* Importance: It is one of the best selling [[cancer]] drugs of all time. It was the drug to be approved from the tyrosine kinase inhibitor class of drugs. It is very specific receptor tyrosine kinase (RTK) inhibitor, binding to Abl, PDGFR and KIT with far greater specificity than other RTKs, helping explain its relatively low impact side effect profile. Has generated significant controversy due to its nearly $65,000 per year cost at a time when global health care budgets are being stretched thin.<ref>A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, November 2, 2009</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>* Importance: It is one of the best selling [[cancer]] drugs of all time. It was the drug to be approved from the tyrosine kinase inhibitor class of drugs. It is very specific receptor tyrosine kinase (RTK) inhibitor, binding to Abl, PDGFR and KIT with far greater specificity than other RTKs, helping explain its relatively low impact side effect profile. Has generated significant controversy due to its nearly $65,000 per year cost at a time when global health care budgets are being stretched thin.<ref>A Conversation With Brian J. Druker, M.D., Researcher Behind the Drug Gleevec by Claudia Dreifus, The New York Times, November 2, 2009</ref></div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>* See also [[Bcr-Abl and Imatinib (STI571 or Gleevec)]]</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> </table>

Alexander Berchansky http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705804&oldid=prev Jaime Prilusky at 11:22, 17 January 2017 2017-01-17T11:22:35Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 11:22, 17 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 1:</td> <td colspan="2" class="diff-lineno">Line 1:</td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><StructureSection load='' size='450' side='right' scene='Imatinib/Imatinib/2' caption='Imatinib, also known as Gleevec ([[2hyy]])'></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><StructureSection load='' size='450' side='right' scene='Imatinib/Imatinib/2' caption='Imatinib, also known as Gleevec ([[2hyy]])<ins style="color: red; font-weight: bold; text-decoration: none;">' pspeed='8</ins>'></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>__TOC__</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>__TOC__</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Better Known as: Gleevec===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Better Known as: Gleevec===</div></td></tr> </table>

Jaime Prilusky http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705803&oldid=prev Joel L. Sussman at 09:07, 17 January 2017 2017-01-17T09:07:57Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 09:07, 17 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 11:</td> <td colspan="2" class="diff-lineno">Line 11:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Mechanism of Action===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Mechanism of Action===</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene> (<scene name='43/430063/1/1'>"DFG triad" without spin</scene>). A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene> (<scene name='43/430063/1/1<ins style="color: red; font-weight: bold; text-decoration: none;">' pspeed='8</ins>'>"DFG triad" without spin</scene>). A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> </table>

Joel L. Sussman http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705802&oldid=prev Alexander Berchansky at 07:52, 17 January 2017 2017-01-17T07:52:03Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 07:52, 17 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 11:</td> <td colspan="2" class="diff-lineno">Line 11:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Mechanism of Action===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Mechanism of Action===</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene> <ins style="color: red; font-weight: bold; text-decoration: none;">(<scene name='43/430063/1/1'>"DFG triad" without spin</scene>)</ins>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> </table>

Alexander Berchansky http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705639&oldid=prev Joel L. Sussman at 15:24, 15 January 2017 2017-01-15T15:24:43Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 15:24, 15 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 11:</td> <td colspan="2" class="diff-lineno">Line 11:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Mechanism of Action===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Mechanism of Action===</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by <del style="color: red; font-weight: bold; text-decoration: none;">with </del>H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> </table>

Joel L. Sussman http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705637&oldid=prev Joel L. Sussman at 15:22, 15 January 2017 2017-01-15T15:22:06Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 15:22, 15 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 1:</td> <td colspan="2" class="diff-lineno">Line 1:</td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><StructureSection load='' size='<del style="color: red; font-weight: bold; text-decoration: none;">350</del>' side='right' scene='Imatinib/Imatinib/2' caption='Imatinib, also known as Gleevec ([[2hyy]])'></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><StructureSection load='' size='<ins style="color: red; font-weight: bold; text-decoration: none;">450</ins>' side='right' scene='Imatinib/Imatinib/2' caption='Imatinib, also known as Gleevec ([[2hyy]])'></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>__TOC__</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>__TOC__</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Better Known as: Gleevec===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Better Known as: Gleevec===</div></td></tr> </table>

Joel L. Sussman http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705593&oldid=prev Joel L. Sussman at 12:59, 15 January 2017 2017-01-15T12:59:53Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 12:59, 15 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 13:</td> <td colspan="2" class="diff-lineno">Line 13:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><del style="color: red; font-weight: bold; text-decoration: none;"><scene name='43/430063/Mdfg/2'>TextToBeDisplayed</scene></del></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td></tr> </table>

Joel L. Sussman http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705592&oldid=prev Joel L. Sussman at 12:58, 15 January 2017 2017-01-15T12:58:24Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 12:58, 15 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 13:</td> <td colspan="2" class="diff-lineno">Line 13:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene></div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div> </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='43/430063/Mdfg/2'>TextToBeDisplayed</scene></ins></div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div> </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td></tr> </table>

Joel L. Sussman http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705589&oldid=prev Joel L. Sussman at 12:51, 15 January 2017 2017-01-15T12:51:48Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 12:51, 15 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 13:</td> <td colspan="2" class="diff-lineno">Line 13:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><del style="color: red; font-weight: bold; text-decoration: none;"><scene name='43/430063/4/3'>TextToBeDisplayed</scene></del></div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div> </div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>& the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td></tr> </table>

Joel L. Sussman http://52.214.119.220/wiki/index.php?title=Imatinib&diff=2705586&oldid=prev Joel L. Sussman at 12:49, 15 January 2017 2017-01-15T12:49:04Z

<p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 12:49, 15 January 2017</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 13:</td> <td colspan="2" class="diff-lineno">Line 13:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell, <scene name='Imatinib/Bcr-bl/1'>producing the kinase, BCR-Abl</scene>. Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, BCR-Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding in the ATP binding site and stabilizing the inactive conformation of BCR-Abl, in which the well known <scene name='Imatinib/Dfg/1'>"DFG triad" is in the "out" conformation</scene>. A critically important residue, Thr 315, is known as <scene name='Imatinib/Gate/2'>the gatekeeper residue</scene>. In the inactive DFG out conformation, <scene name='Imatinib/Gate_imat/3'>Thr 315 shifts to allow binding of Imatinib</scene> and the <scene name='Imatinib/Activation/1'>activation loop</scene> loops back over the top of the protein . It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in BCR-Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. Imatinib resistant forms of BCR-Abl often have mutations at this gatekeeper position, the most prominent being T315I.<ref>PMID: 20072125</ref> In BCR-Abl, <scene name='Imatinib/Bound_imat/7'>Imatinib is bound</scene> by with H-bonds to residues Met 318, Thr 315, Glu 286, Asp 381, Ile 380 & His 361 along with hydrophobic interactions with residues Ile 360, Ala 380, Met 290, Val 299, Lys 271, Ala 269, Val 256, & Phe 317 firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase.<ref>doi:10.1107/S0907444906047287</ref></div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, & the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>To see <scene name='Dasatinib/Mtot/2'>morphs of the movement</scene> of key structural elements Click: <scene name='Dasatinib/Mdfg/3'>DFG Movement</scene>, <scene name='Dasatinib/Mpl/4'>P-Loop Movement</scene>, </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div> </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div><ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='43/430063/4/3'>TextToBeDisplayed</scene></ins></div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div> </div></td></tr> <tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>& the <scene name='Dasatinib/Mact/1'>Activation Loop Movement</scene>.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>===Pharmacokinetics===</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div><table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%"> </div></td></tr> </table>

Joel L. Sussman