2. Academic Validation
  3. Selective and Potent PROTAC Degraders of c-Src Kinase

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

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.

Figures
Products