2. Academic Validation
  3. Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2

Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2

  • J Med Chem. 2021 May 13;64(9):5447-5469. doi: 10.1021/acs.jmedchem.0c01771.
Michael J Roy 1 2,  Amelia Vom 1 2,  Toru Okamoto 1 2,  Brian J Smith 1 2,  Richard W Birkinshaw 1 2,  Hong Yang 1 2,  Houda Abdo 1 2,  Christine A White 1 2,  David Segal 1,  David C S Huang 1 2,  Jonathan B Baell 1 2,  Peter M Colman 1 2,  Peter E Czabotar 1 2,  Guillaume Lessene 1 2 3
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Parkville, VIC 3050, Australia.
  • 3 Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC 3050, Australia.
PMID: 33904752 DOI: 10.1021/acs.jmedchem.0c01771
Abstract

The Bcl-2 Family of proteins (including the prosurvival proteins Bcl-2, BCL-XL, 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-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/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-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and Bcl-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.

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