Selective and Potent PROTAC Degraders of c-Src Kinase

  • ACS Chem Biol. 2024 Jan 19;19(1):110-116. doi: 10.1021/acschembio.3c00548.
Wuxiang Mao  1 ,  Nathalie M Vandecan  1 ,  Christopher R Bingham  1 ,  Pui Ki Tsang  1 ,  Peter Ulintz  2 ,  Rachel Sexton  1 ,  Daniel A Bochar  1 ,  Sofia D Merajver  2 ,  Matthew B Soellner  1  2
Affiliations
  • 1. Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Internal Medicine, University of Michigan, 1500 E. Medical Avenue, Ann Arbor, Michigan 48109, United States.
PMID: 38113191 DOI: 10.1021/acschembio.3c00548
Abstract

Using dasatinib linked to E3 Ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib, the c-Src-directed ligand, with a conformation-selective analogue that stabilizes the αC-helix-out conformation of c-Src. Using the αC-helix-out ligand, we identified a PROTAC that is potent and selective for c-Src. We demonstrated a high degree of catalysis with our c-Src PROTACs. Using our c-Src PROTACs, we identified pharmacological advantages of c-Src degradation compared to inhibition with respect to Cancer cell proliferation.

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