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Structure of human Bcl-xL in complex with small molecule inhibitor
Structural highlights
DiseaseBCL2_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. FunctionBCL2_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] 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.[2] [3] Isoform Bcl-X(S) promotes apoptosis.[4] [5] Publication Abstract from PubMedEvasion of apoptosis is a hallmark of cancer. Deregulation of BCL-XL, a member of the BCL-2 family of proteins, has been linked to the development of various tumor types. This study presents the design and synthesis of BCL-XL inhibitors with novel mono- and bicyclic cores. The new structural features were optimized to combine high binding efficiency with the opening of diverse novel vectors for additional modifications. The lead compounds exhibited picomolar affinities and significant cellular potency in the BCL-XL-dependent MOLT-4 cell line, which also translated into marked tumor growth inhibition in a xenograft study. These findings highlight the potential of BCL-XL inhibitors as therapeutic agents in cancer treatment by targeting the apoptotic intrinsic pathway. Structure-Based Discovery of Potent BCL-XL Inhibitors through Rescaffolding.,Timari MP, Paczal A, Herner A, Molnar M, Madarasz Z, Nyerges M, Bedford ST, Brooks T, Davidson J, Daniels Z, Dodsworth M, Dokurno P, Murray JB, Parsons R, Sanders E, Smith J, Webb P, Whitehead N, Hubbard RE, Starck JB, Maragno AL, Le Toumelin-Braizat G, Bresson L, Rocchetti F, Demarles D, Colland F, Geneste O, Kotschy A, Novak T J Med Chem. 2026 Jun 12. doi: 10.1021/acs.jmedchem.6c00865. PMID:42283755[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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