9aqz

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of Bcl-xL in complex with a small molecule inhibitor

Structural highlights

9aqz is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.961Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

B2CL1_HUMAN Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.^[1] ^[2] Isoform Bcl-X(S) promotes apoptosis.^[3] ^[4]

Publication Abstract from PubMed

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X(L)) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-X(L) inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X(L) inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X(L)-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-X(L)-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X(L)-targeting agent to enter human clinical trials.

BCL-X(L)-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.,Judd AS, Bawa B, Buck WR, Tao ZF, Li Y, Mitten MJ, Bruncko M, Catron N, Doherty G, Durbin KR, Enright B, Frey R, Haasch D, Haman S, Haight AR, Henriques TA, Holms J, Izeradjene K, Judge RA, Jenkins GJ, Kunzer A, Leverson JD, Martin RL, Mitra D, Mittelstadt S, Nelson L, Nimmer P, Palma J, Peterson R, Phillips DC, Ralston SL, Rosenberg SH, Shen X, Song X, Vaidya KR, Wang X, Wang J, Xiao Y, Zhang H, Zhang X, Blomme EA, Boghaert ER, Kalvass JC, Phillips A, Souers AJ Sci Adv. 2024 Oct 4;10(40):eado7120. doi: 10.1126/sciadv.ado7120. Epub 2024 Oct , 4. PMID:39365864^[5]

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

References

↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
↑ Judd AS, Bawa B, Buck WR, Tao ZF, Li Y, Mitten MJ, Bruncko M, Catron N, Doherty G, Durbin KR, Enright B, Frey R, Haasch D, Haman S, Haight AR, Henriques TA, Holms J, Izeradjene K, Judge RA, Jenkins GJ, Kunzer A, Leverson JD, Martin RL, Mitra D, Mittelstadt S, Nelson L, Nimmer P, Palma J, Peterson R, Phillips DC, Ralston SL, Rosenberg SH, Shen X, Song X, Vaidya KR, Wang X, Wang J, Xiao Y, Zhang H, Zhang X, Blomme EA, Boghaert ER, Kalvass JC, Phillips A, Souers AJ. BCL-X(L)-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors. Sci Adv. 2024 Oct 4;10(40):eado7120. PMID:39365864 doi:10.1126/sciadv.ado7120

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9aqz"

Categories: Homo sapiens | Large Structures | Judd AS | Judge RA

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[9aqz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9AQZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9AQZ FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.961&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AFG:(3M)-3-(1-{[(1r,3R,5S,7r)-adamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic+acid'>A1AFG</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AFG:3-[1-(1-adamantylmethyl)-5-methyl-pyrazol-4-yl]-6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]pyridine-2-carboxylic+acid'>A1AFG</scene>, <scene name='pdbligand=CD:CADMIUM+ION'>CD</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=9aqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9aqz OCA], [https://pdbe.org/9aqz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9aqz RCSB], [https://www.ebi.ac.uk/pdbsum/9aqz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9aqz ProSAT]</span></td></tr>
 </table>

9aqz

From Proteopedia

Current revision

Crystal structure of Bcl-xL in complex with a small molecule inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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