Chemoselective lysine-reactive electrophiles for covalent targeting of proteins

DOI
  • Shindo Naoya
    Graduate School of Pharmaceutical Sciences, Kyushu University Faculty of Pharmaceutical Sciences, Hokkaido University
  • Tanaka Yudai
    Graduate School of Pharmaceutical Sciences, Kyushu University
  • Tanigawa Atsuya
    Graduate School of Pharmaceutical Sciences, Kyushu University
  • Ojida Akio
    Graduate School of Pharmaceutical Sciences, Kyushu University

Bibliographic Information

Other Title
  • コバレントドラッグを指向したリジン選択的反応化学の開発

Description

Covalent drugs exert potent and sustained pharmacological efficacy through irreversible inhibition of the target protein. While cysteine-targeting covalent drug discovery has been a powerful strategy, the target scope is limited due to the low abundance of cysteines in the proteome. Covalent targeting of lysines would greatly expand the opportunity. However, the scarcity of aminophilic electrophiles with high chemoselectivity and stability under live cell conditions prevents progress. Here, we disclose 2-cyanoarenesulfonamides (CNS) as novel aminophilic warheads. CNS exhibits highly chemoselective and tunable reactivity toward amines through a novel mechanism involving ring-chain tautomerism. We designed CNS-based covalent inhibitors targeting Lys58 of heat shock protein 90 (Hsp90) . The probes displayed good inhibitory activity and selectivity toward Hsp90 in live cells, demonstrating the utility of CNS as lysine-targeting electrophiles.

Journal

  • MEDCHEM NEWS

    MEDCHEM NEWS 34 (2), 88-92, 2024-05-01

    The Pharmaceutical Society of Japan

Keywords

Details 詳細情報について

  • CRID
    1390862943886462592
  • DOI
    10.14894/medchem.34.2_88
  • ISSN
    24328626
    24328618
  • Text Lang
    ja
  • Data Source
    • JaLC
  • Abstract License Flag
    Disallowed

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