9gip | pdb_00009gip
BFL1 covalently bound to inhibitor compound 7
Structural highlights
FunctionB2LA1_HUMAN Retards apoptosis induced by IL-3 deprivation. May function in the response of hemopoietic cells to external signals and in maintaining endothelial survival during infection (By similarity). Publication Abstract from PubMedBFL1, a member of the antiapoptotic BCL2 family, has been relatively understudied compared to its counterparts despite evidence of its overexpression in various hematological malignancies. Across two articles, we describe the development of BFL1 in vivo tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound 6.(22) This work reports the structure-based optimization of compound 6 into a series of BFL1 inhibitors selective over the other BCL2 family members, with low nanomolar cellular activity when combined with AZD5991, exemplified by compound 20. Compound 20 demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the in vivo study, BFL1 stabilization and cleaved caspase 3 activation were observed in a dose-dependent manner. In addition, the enzymatic turnover studies with the BFL1 protein showed that compound 20 stabilized the protein, extending the half-life to 10.8 h. Structure-Based Discovery of a Series of Covalent, Orally Bioavailable, and Selective BFL1 Inhibitors.,Palisse A, Cheung T, Blokhuis A, Cogswell T, Martins BS, Riemens R, Schellekens R, Battocchio G, Jansen C, Cottee MA, Ornell K, Sacchetto C, Leon L, van Hoek-Emmelot M, Bostock M, Brauer BL, Beaumont K, Lucas SCC, Ahmed S, Blackwell JH, Borjesson U, Gohlke A, Gramatikov IMT, Hargreaves D, van Hoeven V, Kantae V, Kupcova L, Milbradt AG, Seneviratne U, Su N, Vales J, Wang H, White MJ, Kinzel O J Med Chem. 2024 Dec 6. doi: 10.1021/acs.jmedchem.4c01995. PMID:39641779[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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