Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

J Med Chem. 2024 Jul 11;67(13):11209-11225. doi: 10.1021/acs.jmedchem.4c00781. Epub 2024 Jun 25.

Abstract

Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.

MeSH terms

  • Crystallography, X-Ray
  • Cysteine* / chemistry
  • Drug Design*
  • Humans
  • Minor Histocompatibility Antigens
  • Models, Molecular
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Small Molecule Libraries* / chemistry
  • Small Molecule Libraries* / pharmacology
  • Structure-Activity Relationship

Substances

  • Small Molecule Libraries
  • Cysteine
  • BCL2-related protein A1
  • Proto-Oncogene Proteins c-bcl-2
  • Minor Histocompatibility Antigens