8RPO

BFL1 in complex with a reversible covalent ligand

これはPDB形式変換不可エントリーです。

8RPO の概要

• エントリーDOI: 10.2210/pdb8rpo/pdb
• 分子名称: Bcl-2-related protein A1, (~{E})-2-cyano-3-(2-dimethylphosphorylphenyl)-~{N}-[[1-[4-(trifluoromethyl)phenyl]cyclopropyl]methyl]prop-2-enamide (3 entities in total)
• 機能のキーワード: bfl bcl covalent, 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: 17889.29

構造登録者

Hargreaves, D. (登録日: 2024-01-16, 公開日: 2024-07-03)

主引用文献

Lucas, S.C.C.,Blackwell, J.H.,Borjesson, U.,Hargreaves, D.,Milbradt, A.G.,Ahmed, S.,Bostock, M.J.,Guerot, C.,Gohlke, A.,Kinzel, O.,Lamb, M.L.,Selmi, N.,Stubbs, C.J.,Su, N.,Su, Q.,Luo, H.,Xiong, T.,Zuo, X.,Bazzaz, S.,Bienstock, C.,Centrella, P.A.,Denton, K.E.,Gikunju, D.,Guie, M.A.,Guilinger, J.P.,Hupp, C.,Keefe, A.D.,Satoh, T.,Zhang, Y.,Rivers, E.L.
Identification and Evaluation of Reversible Covalent Binders to Cys55 of Bfl-1 from a DNA-Encoded Chemical Library Screen.
Acs Med.Chem.Lett., 15:791-797, 2024

PubMed Abstract: Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.

PubMed: 38894895
DOI: 10.1021/acsmedchemlett.4c00113

実験手法

X-RAY DIFFRACTION (1.791 Å)