2. Academic Validation
  3. Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

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

  • J Med Chem. 2024 Jun 25. doi: 10.1021/acs.jmedchem.4c00781.
Simon C C Lucas 1,  Alexander G Milbradt 2,  J Henry Blackwell 1,  Silvia Bonomo 1,  Andrew Brierley 3,  Doyle J Cassar 4,  Jared Freeman 5,  Thomas E Hadfield 1,  Lucas A Morrill 6,  Rick Riemens 7,  Sunil Sarda 3,  Stefan Schiesser 8,  Daniel Wiktelius 9,  Samiyah Ahmed 10,  Mark J Bostock 2,  Ulf Börjesson 11,  Claudia De Fusco 1,  Carine Guerot 4,  David Hargreaves 2,  Sarah Hewitt 2,  Michelle L Lamb 6,  Nancy Su 12,  Ryan Whatling 2,  Matthew Wheeler 2,  Jason G Kettle 4
Affiliations

Affiliations

  • 1 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3 Compound Synthesis and Management, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 4 Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 5 Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolic Disorders (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 6 Medicinal Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 7 Medicinal Chemistry, Oncology R&D, Acerta B. V., a Part of the AstraZeneca Group, Oss 5349, The Netherlands.
  • 8 Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 9 Compound Synthesis and Management, Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 10 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 11 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-43183, Sweden.
  • 12 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
PMID: 38916990 DOI: 10.1021/acs.jmedchem.4c00781
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.

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