Hydrophobic Tagging-Induced Degradation of PDEδ in Colon Cancer Cells

  • ACS Med Chem Lett. 2022 Jan 12;13(2):298-303. doi: 10.1021/acsmedchemlett.1c00670.
Menglu Guo  1 ,  Shipeng He  2 ,  Junfei Cheng  1 ,  Yu Li  1 ,  Guoqiang Dong  1 ,  Chunquan Sheng  1
Affiliations
  • 1. School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 2. Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
PMID: 35178186 DOI: 10.1021/acsmedchemlett.1c00670
Abstract

The development of KRAS-PDEδ protein-protein interaction (PPI) inhibitors is generally hampered by limited antitumor activity. Herein, the first hydrophobic tagging (HyT)-based PDEδ degraders were designed. Compound 17c efficiently bound to PDEδ and induced degradation of PDEδ in SW480 colon Cancer cells. As compared with PDEδ inhibitor deltazinone, HyT-based degrader 17c exhibited improved antitumor activity toward KRAS mutant Cancer cells. This study highlighted the potential of HyT as a valuable chemical tool for tumorigenic PDEδ knockdown, which could be developed into a promising strategy for antitumor drug discovery.