7jgw
Crystal structure of BCL-XL in complex with COMPOUND 1620116, CRYSTAL FORM 1
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 PubMedLimited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold (43) with potent sBCL-2 activity (IC50 30 nM). Human BCL-XL potency (IC50 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis. Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.,Nguyen W, Lee EF, Evangelista M, Lee M, Harris TJ, Colman PM, Smith NA, Williams LB, Jarman KE, Lowes KN, Haeberli C, Keiser J, Smith BJ, Fairlie WD, Sleebs BE ACS Infect Dis. 2021 Feb 1. doi: 10.1021/acsinfecdis.0c00700. PMID:33523649[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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