2. Academic Validation
  3. Covalent Stapling of the Cereblon Sensor Loop Histidine Using Sulfur-Heterocycle Exchange

Covalent Stapling of the Cereblon Sensor Loop Histidine Using Sulfur-Heterocycle Exchange

  • ACS Med Chem Lett. 2023 Oct 24;14(11):1576-1581. doi: 10.1021/acsmedchemlett.3c00371.
Justin T Cruite 1 2,  Radosław P Nowak 1 2,  Katherine A Donovan 2 3,  Scott B Ficarro 4 5,  Huang Huang 1 2,  Hu Liu 1 2,  Yingpeng Liu 1 2,  Jarrod A Marto 4 5,  Rebecca J Metivier 1,  Eric S Fischer 1 2 3,  Lyn H Jones 1 2
Affiliations

Affiliations

  • 1 Center for Protein Degradation, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 4 Department of Cancer Biology, Department of Oncologic Pathology, Blais Proteomics Center, and Center for Emergent Drug Targets, Dana-Farber Cancer Institute, Boston Massachusetts 02215, United States.
  • 5 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 37974938 DOI: 10.1021/acsmedchemlett.3c00371
Abstract

Site-specific modification of amino acid residues in protein binding pockets using sulfonyl exchange chemistry expands the druggable proteome by enabling the development of covalent modulators that target residues beyond cysteine. Sulfonyl fluoride and triazole electrophiles were incorporated previously into the Cereblon (CRBN) molecular glue degrader EM12, to covalently engage His353 within the CRBN sensor loop, but these probes had poor human plasma stability. Attenuation of intrinsic reactivity through the development of sulfonyl pyrazoles, imidazoles, and nucleobases enhanced plasma stability, and several compounds retained efficient labeling of His353. For example, sulfonyl imidazole EM12-SO2Im covalently blocked the CRBN binding site and possessed excellent metabolic stability in human plasma, liver microsomes, and hepatocytes. These results highlight the potential suitability of sulfonyl imidazole and related sulfur(VI)-diazole exchange (SuDEx) warheads for covalent drug development and further exemplify the therapeutic promise of site-specific histidine targeting.

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