9GIT

BFL1 covalently bound to inhibitor compound 43

これはPDB形式変換不可エントリーです。

9GIT の概要

• エントリーDOI: 10.2210/pdb9git/pdb
• 分子名称: 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)
• 機能のキーワード: bfl, bcl, covalent, inhibitor, apoptosis
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18052.00

構造登録者

Cottee, M.A. (登録日: 2024-08-19, 公開日: 2024-12-18, 最終更新日: 2025-01-08)

主引用文献

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

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: 39641779
DOI: 10.1021/acs.jmedchem.4c01995

実験手法

X-RAY DIFFRACTION (1.145 Å)