2. Academic Validation
  3. Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors

Structure-Based Optimization of a Series of Covalent, Cell Active Bfl-1 Inhibitors

  • J Med Chem. 2024 Sep 26;67(18):16455-16479. doi: 10.1021/acs.jmedchem.4c01288.
Simon C C Lucas 1,  J Henry Blackwell 1,  Ulf Börjesson 2,  David Hargreaves 3,  Alexander G Milbradt 3,  Mark J Bostock 3,  Samiyah Ahmed 4,  Kevin Beaumont 5,  Tony Cheung 6,  Sylvain Demanze 7,  Andrea Gohlke 3,  Carine Guerot 7,  Afreen Haider 3,  Vasudev Kantae 3,  Gregory W Kauffman 8,  Olaf Kinzel 9,  Lea Kupcova 3,  Michael D Lainchbury 1,  Michelle L Lamb 8,  Leonardo Leon 6,  Adeline Palisse 9,  Claudia Sacchetto 10,  R Ian Storer 1,  Nancy Su 11,  Clare Thomson 7,  John Vales 3,  Yunhua Chen 12,  Xiaolong Hu 12
Affiliations

Affiliations

  • 1 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2 Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 3 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 4 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 5 DMPK, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 6 Oncology Bioscience, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 7 Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 8 Medicinal Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 9 Medicinal Chemistry, Oncology R&D, Acerta B.V., a Member of the AstraZeneca Group, Oss 5349, The Netherlands.
  • 10 Bioscience, Oncology R&D, Acerta B.V., a Member of the AstraZeneca Group, Oss 5349, The Netherlands.
  • 11 Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
  • 12 Pharmaron Beijing Co., Ltd., Beijing 100176, P. R. China.
PMID: 39291659 DOI: 10.1021/acs.jmedchem.4c01288
Abstract

Bfl-1, a member of the Bcl-2 Family of proteins, plays a crucial role in Apoptosis regulation and has been implicated in Cancer cell survival and resistance to venetoclax therapy. Due to the unique cysteine residue in the BH3 binding site, the development of covalent inhibitors targeting Bfl-1 represents a promising strategy for Cancer treatment. Herein, the optimization of a covalent cellular tool from a lead-like hit using structure based design is described. Informed by a reversible X-ray fragment screen, the strategy to establish interactions with a key glutamic acid residue (Glu78) and optimize binding in a cryptic pocket led to a 1000-fold improvement in biochemical potency without increasing reactivity of the warhead. Compound (R,R,S)-26 has a kinact/KI of 4600 M-1 s-1, shows <1 μM Caspase activation in a cellular assay and cellular target engagement, and has good physicochemical properties and a promising in vivo profile.

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