9aqz
From Proteopedia
Crystal structure of Bcl-xL in complex with a small molecule inhibitor
Structural highlights
FunctionB2CL1_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 PubMedOverexpression 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
| ||||||||||||||||||||
