Bicyclobutane carboxylic amide as a cysteine-directed strained electrophile for selective targeting of proteins

Naoya Shindo, Akio Ojida, Keisuke Tokunaga, Mami Sato, Keiko Kuwata, Chizuru Miura, Hirokazu Fuchida, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Expanding the repertoire of electrophiles with unique reactivity features would facilitate the development of covalent inhibitors with desirable reactivity profiles. We herein introduce bicyclo[1.1.0]butane (BCB) carboxylic amide as a new class of thiol-reactive electrophiles for selective and irreversible inhibition of targeted proteins. We first streamlined the synthetic routes to generate a variety of BCB amides. The strain-driven nucleophilic addition to BCB amides proceeded chemoselectively with cysteine thiols under neutral aqueous conditions, the rate of which was significantly slower than that of acrylamide. This reactivity profile of BCB amide was successfully exploited to develop covalent ligands targeting Bruton's tyrosine kinase (BTK). By tuning BCB amide reactivity and optimizing its disposition on the ligand, we obtained a selective covalent inhibitor of BTK. The in-gel activitybased protein profiling and mass spectrometry-based chemical proteomics revealed that the selected BCB amide had a higher target selectivity for BTK in human cells than did a Michael acceptor probe. Further chemical proteomic study revealed that BTK probes bearing different classes of electrophiles exhibited distinct off-target profiles. This result suggests that incorporation of BCB amide as a cysteine-directed electrophile could expand the capability to develop covalent inhibitors with the desired proteome reactivity profile.

Original languageEnglish
Pages (from-to)18522-18531
Number of pages10
JournalJournal of the American Chemical Society
Volume142
Issue number43
DOIs
Publication statusPublished - Oct 28 2020

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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