8RPO

BFL1 in complex with a reversible covalent ligand

This is a non-PDB format compatible entry.

Summary for 8RPO

• Entry DOI: 10.2210/pdb8rpo/pdb
• Descriptor: 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)
• Functional Keywords: bfl bcl covalent, apoptosis
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 17889.29

Authors

Hargreaves, D. (deposition date: 2024-01-16, release date: 2024-07-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.791 Å)