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
  • 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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