2. Academic Validation
  3. Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer

Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer

  • J Med Chem. 2023 Dec 14;66(23):16168-16186. doi: 10.1021/acs.jmedchem.3c01521.
Xufen Yu 1 2,  Dongxu Li 3 4,  Jithesh Kottur 1 2,  Huen Suk Kim 1 2,  Laura E Herring 5,  Yao Yu 3 4 6 7 8,  Ling Xie 4,  Xiaoping Hu 1 2,  Xian Chen 4,  Ling Cai 3 6 7,  Jing Liu 1 2,  Aneel K Aggarwal 2,  Gang Greg Wang 3 4 5 6 7 8,  Jian Jin 1 2
Affiliations

Affiliations

  • 1 Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 2 Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 5 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 6 Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina 27710, United States.
  • 7 Department of Pathology, Duke University School of Medicine, Durham, North Carolina 27710, United States.
  • 8 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710, United States.
PMID: 38019706 DOI: 10.1021/acs.jmedchem.3c01521
Abstract

As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein-protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure-activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including 11 (MS132), a highly potent and selective von Hippel-Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and 25, a Cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1. Furthermore, by conducting site-directed mutagenesis studies, we determined that WDR5 K296, but not K32, was involved in the PROTAC-induced WDR5 degradation. Collectively, these studies resulted in a highly effective WDR5 degrader, which could be a potential therapeutic for pancreatic Cancer and several potentially useful tool compounds.

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