2. Academic Validation
  3. Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6

Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6

  • J Am Chem Soc. 2023 May 10;145(18):10015-10021. doi: 10.1021/jacs.2c12240.
Kurt S Van Horn 1,  Dongju Wang 1 2,  Daniel Medina-Cleghorn 1,  Peter S Lee 1,  Clifford Bryant 1,  Chad Altobelli 1,  Priyadarshini Jaishankar 1,  Kevin K Leung 1,  Raymond A Ng 3,  Andrew J Ambrose 1,  Yinyan Tang 1,  Michelle R Arkin 1,  Adam R Renslo 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94143, United States.
  • 2 School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 3 Chempartner Corporation, 280 Utah Avenue, South San Francisco, California 94080, United States.
PMID: 37104712 DOI: 10.1021/jacs.2c12240
Abstract

Caspases are a family of cysteine-dependent proteases with important cellular functions in inflammation and Apoptosis, while also implicated in human diseases. Classical chemical tools to study Caspase functions lack selectivity for specific Caspase family members due to highly conserved active sites and catalytic machinery. To overcome this limitation, we targeted a non-catalytic cysteine residue (C264) unique to caspase-6 (C6), an enigmatic and understudied Caspase isoform. Starting from disulfide ligands identified in a cysteine trapping screen, we used a structure-informed covalent ligand design to produce potent, irreversible inhibitors (3a) and chemoproteomic probes (13-t) of C6 that exhibit unprecedented selectivity over other Caspase family members and high proteome selectivity. This approach and the new tools described will enable rigorous interrogation of the role of caspase-6 in developmental biology and in inflammatory and neurodegenerative diseases.

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