6UVH

Crystal structure of BCL-XL bound to compound 15: (R)-2-(3-(2-((4'-Chloro-[1,1'-biphenyl]-2-yl)methyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-3-(4-methylbenzyl)ureido)-3-((cyclohexylmethyl)sulfonyl)propanoic acid

Summary for 6UVH

• Entry DOI: 10.2210/pdb6uvh/pdb
• Descriptor: Bcl-2-like protein 1, 1,2-ETHANEDIOL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: apoptosis, bcl-2 family, bcl-xl, inhibitor, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 74951.43

Authors

Roy, M.J.,Lessene, G.,Czabotar, P.E. (deposition date: 2019-11-02, release date: 2021-05-05, Last modification date: 2023-10-11)

Primary citation

Roy, M.J.,Vom, A.,Okamoto, T.,Smith, B.J.,Birkinshaw, R.W.,Yang, H.,Abdo, H.,White, C.A.,Segal, D.,Huang, D.C.S.,Baell, J.B.,Colman, P.M.,Czabotar, P.E.,Lessene, G.
Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-X L and BCL-2.
J.Med.Chem., 64:5447-5469, 2021

PubMed Abstract: The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-X, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-X, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-X/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-X. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-X. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-X and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC)) and displaying mechanism-based killing in cells engineered to depend on BCL-X for survival.

PubMed: 33904752
DOI: 10.1021/acs.jmedchem.0c01771

Experimental method

X-RAY DIFFRACTION (2.19 Å)