Summary for 9GIT
| Entry DOI | 10.2210/pdb9git/pdb |
| Descriptor | Bcl-2-related protein A1, (3~{S})-3-[[4-[(1~{R},3~{R})-3-[[(3~{R})-1,1-bis(oxidanylidene)thiolan-3-yl]carbamoylamino]cyclopentyl]oxy-3-fluoranyl-phenyl]-propanoyl-amino]-3-(4-chlorophenyl)propanamide (3 entities in total) |
| Functional Keywords | bfl, bcl, covalent, inhibitor, apoptosis |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18052.00 |
| Authors | Cottee, M.A. (deposition date: 2024-08-19, release date: 2024-12-18, Last modification date: 2025-01-08) |
| Primary citation | Palisse, A.,Cheung, T.,Blokhuis, A.,Cogswell, T.,Martins, B.S.,Riemens, R.,Schellekens, R.,Battocchio, G.,Jansen, C.,Cottee, M.A.,Ornell, K.,Sacchetto, C.,Leon, L.,van Hoek-Emmelot, M.,Bostock, M.,Brauer, B.L.,Beaumont, K.,Lucas, S.C.C.,Ahmed, S.,Blackwell, J.H.,Borjesson, U.,Gohlke, A.,Gramatikov, I.M.T.,Hargreaves, D.,van Hoeven, V.,Kantae, V.,Kupcova, L.,Milbradt, A.G.,Seneviratne, U.,Su, N.,Vales, J.,Wang, H.,White, M.J.,Kinzel, O. Structure-Based Discovery of a Series of Covalent, Orally Bioavailable, and Selective BFL1 Inhibitors. J.Med.Chem., 67:22055-22079, 2024 Cited by PubMed Abstract: BFL1, 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 tools. The first article describes the hit identification from a covalent fragment library and the subsequent evolution from the hit to compound . This work reports the structure-based optimization of compound into a series of BFL1 inhibitors selective over the other BCL2 family members, with low cellular activity when combined with AZD5991, exemplified by compound . Compound demonstrated a cell death phenotype in SUDHL1 and OCILY10 cell lines and in the 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 stabilized the protein, extending the half-life to 10.8 h. PubMed: 39641779DOI: 10.1021/acs.jmedchem.4c01995 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.145 Å) |
Structure validation
Download full validation report
