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7lhb

From Proteopedia

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Current revision

Crystal structure of Bcl-2 in complex with prodrug ABBV-167

Structural highlights

7lhb is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.068Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BCL2_HUMAN Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.

Function

BCL2_HUMAN Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).^[1]

Publication Abstract from PubMed

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. While a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Expanding the repertoire for "large small molecules" : Prodrug ABBV-167 efficiently converts to venetoclax with reduced food effect in healthy volunteers.,Salem AH, Tao ZF, Bueno OF, Chen J, Chen S, Edalji R, Elmore SW, Fournier KM, Harper KC, Hong R, Jenkins GJ, Ji J, Judge RA, Kalvass JC, Klix RC, Ku YY, Leverson JD, Marks RA, Marsh KC, Menon RM, Park CH, Phillips DC, Pu YM, Rosenberg SH, Sanzgiri YD, Sheikh AY, Shi Y, Stolarik D, Suleiman AA, Wang X, Zhang GGZ, Catron ND, Souers AJ Mol Cancer Ther. 2021 Mar 30. pii: 1535-7163.MCT-21-0077. doi:, 10.1158/1535-7163.MCT-21-0077. PMID:33785651^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
↑ Salem AH, Tao ZF, Bueno OF, Chen J, Chen S, Edalji R, Elmore SW, Fournier KM, Harper KC, Hong R, Jenkins GJ, Ji J, Judge RA, Kalvass JC, Klix RC, Ku YY, Leverson JD, Marks RA, Marsh KC, Menon RM, Park CH, Phillips DC, Pu YM, Rosenberg SH, Sanzgiri YD, Sheikh AY, Shi Y, Stolarik D, Suleiman AA, Wang X, Zhang GGZ, Catron ND, Souers AJ. Expanding the repertoire for "large small molecules" : Prodrug ABBV-167 efficiently converts to venetoclax with reduced food effect in healthy volunteers. Mol Cancer Ther. 2021 Mar 30. pii: 1535-7163.MCT-21-0077. doi:, 10.1158/1535-7163.MCT-21-0077. PMID:33785651 doi:http://dx.doi.org/10.1158/1535-7163.MCT-21-0077

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7lhb"

Categories: Homo sapiens | Large Structures | Synthetic construct | Judge RA | Salem AH

@@ Line 3: / Line 3: @@
 <StructureSection load='7lhb' size='340' side='right'caption='[[7lhb]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7lhb]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LHB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LHB FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7lhb]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LHB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LHB FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XZD:Phosphoric+acid+mono-[5-(5-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-{3-nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylaminocarbonyl}-phenoxy)-pyrrolo[2,3-b]pyridin-7-ylmethyl]+ester'>XZD</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.068&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XZD:Phosphoric+acid+mono-[5-(5-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-{3-nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylaminocarbonyl}-phenoxy)-pyrrolo[2,3-b]pyridin-7-ylmethyl]+ester'>XZD</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lhb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lhb OCA], [https://pdbe.org/7lhb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lhb RCSB], [https://www.ebi.ac.uk/pdbsum/7lhb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lhb ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN]] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
+[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
 == Function ==
-[[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN]] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).<ref>PMID:18570871</ref>
+[https://www.uniprot.org/uniprot/BCL2_HUMAN BCL2_HUMAN] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).<ref>PMID:18570871</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 28: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Judge, R A]]
+[[Category: Synthetic construct]]
-[[Category: Salem, A H]]
+[[Category: Judge RA]]
-[[Category: Abbv-167]]
+[[Category: Salem AH]]
-[[Category: Apoptosis]]
-[[Category: Bcl-2]]
-[[Category: Prodrug]]

7lhb

From Proteopedia

Current revision

Crystal structure of Bcl-2 in complex with prodrug ABBV-167

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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