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Sandbox ggc6

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In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out <ref>DOI 10.1016/j.bmcl.2013.01.047</ref>. This compound potentially possess two different binding modes: allosteric binding and hinge binding, and this hypothesis was also supported by the fact that FAK inhibitory potential of compound 22 under the high concentration of ATP was much weaker. The purpose was to facilitate pure allosteric inhibition of FAK by targeting the FAK allosteric site, demonstrating a potential of FAK allosteric inhibitors as antitumor agents. Kinase activity of FAK were selectively inhibited without affecting other kinases and the compound possessed significant FAK kinase inhibitory activities in cell free and cellular assays <ref>DOI 10.1002/ijch.201300024</ref>. Phosphorylation of proteins by kinases is important in communicating signals within a cell and regulating cellular activity, such as cell division <ref> en.wikipedia.org/wiki/tyrosine_kinase </ref>.
In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out <ref>DOI 10.1016/j.bmcl.2013.01.047</ref>. This compound potentially possess two different binding modes: allosteric binding and hinge binding, and this hypothesis was also supported by the fact that FAK inhibitory potential of compound 22 under the high concentration of ATP was much weaker. The purpose was to facilitate pure allosteric inhibition of FAK by targeting the FAK allosteric site, demonstrating a potential of FAK allosteric inhibitors as antitumor agents. Kinase activity of FAK were selectively inhibited without affecting other kinases and the compound possessed significant FAK kinase inhibitory activities in cell free and cellular assays <ref>DOI 10.1002/ijch.201300024</ref>. Phosphorylation of proteins by kinases is important in communicating signals within a cell and regulating cellular activity, such as cell division <ref> en.wikipedia.org/wiki/tyrosine_kinase </ref>.
== Structural highlights ==
== Structural highlights ==
-
<scene name='75/752265/Transferase/8'>Overview of Transferase Structure</scene>. This scene shows the entire 4I4E structure of the PtK2 cell, showing alpha helix structure, beta sheets, and the backbone of the structure. When zooming in, the scene then shows how the compound of pyrazolo[4,3-c][2,1]benzothiazine inhibits the FAK allosteric site. The CPK ligand (compound 22) forms direct and/or water-mediated hydrogen bonds with Glu506, Ser509, and Arg514. These three sites are shown and labeled within the structure. The water mediated Hydrogen bond formed with Glu506 is also shown within the structure.
+
<scene name='75/752265/Transferase/8'>Overview of Transferase Structure</scene>. This scene shows the entire 4I4E structure of the PtK2 cell, showing alpha helix structure, beta sheets, and the backbone of the structure. When zooming in, the scene then shows how the compound of pyrazolo[4,3-c][2,1]benzothiazine inhibits the FAK allosteric site. The CPK ligand (compound 22) forms direct and/or water-mediated hydrogen bonds with Glu506, Ser509, and Arg514. These three sites are shown and labeled within the structure. The water mediated Hydrogen bond formed with Glu506 is also shown within the structure <scene name='75/752265/Transferase/11'>Closer View of Binding Site</scene>.
Color Key:
Color Key:
Cyan-Alpha Helix;
Cyan-Alpha Helix;
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Maroon-All Lys;
Maroon-All Lys;
Black-Ser509;
Black-Ser509;
-
Orange-Cys502. The N-free pyrazole of 22 interacts with Glu500 and Cys502 in the hinge region by two hydrogen bonds <ref>PMID: 23414845</ref><scene name='75/752265/Transferase/11'>Closer View of Binding Site</scene>
+
Orange-Cys502. The N-free pyrazole of 22 interacts with Glu500 and Cys502 in the hinge region by two hydrogen bonds <ref>PMID: 23414845</ref>.
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+
</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

Revision as of 06:26, 1 May 2017

Transferase/Transferase Inhibitor

Caption for this structure

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References

  1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
  3. ↑ en.wikipedia.org/wiki/tyrosine_kinase
  4. ↑ Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, Awazu Y, Isono O, Skene RJ, Hosfield DJ, Miki H, Kawamoto T, Hori A, Baba A. Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg Med Chem Lett. 2013 Mar 15;23(6):1779-85. doi: 10.1016/j.bmcl.2013.01.047., Epub 2013 Jan 26. PMID:23414845 doi:http://dx.doi.org/10.1016/j.bmcl.2013.01.047
  5. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  6. ↑ en.wikipedia.org/wiki/tyrosine_kinase
  7. ↑ Tomita N, Hayashi Y, Suzuki S, Oomori Y, Aramaki Y, Matsushita Y, Iwatani M, Iwata H, Okabe A, Awazu Y, Isono O, Skene RJ, Hosfield DJ, Miki H, Kawamoto T, Hori A, Baba A. Structure-based discovery of cellular-active allosteric inhibitors of FAK. Bioorg Med Chem Lett. 2013 Mar 15;23(6):1779-85. doi: 10.1016/j.bmcl.2013.01.047., Epub 2013 Jan 26. PMID:23414845 doi:http://dx.doi.org/10.1016/j.bmcl.2013.01.047
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