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Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer
Xufen Yu1,2, Dongxu Li3,4, Jithesh Kottur1,2
1Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
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.
Insights
Researchers developed novel WDR5 proteolysis-targeting chimeras (PROTACs) to degrade WDR5, a protein involved in pancreatic cancer. Compound 11 showed potent WDR5 degradation and inhibited pancreatic ductal adenocarcinoma cell proliferation, offering a potential new therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- WDR5 is a crucial chromatin-regulatory scaffolding protein mediating protein-protein interactions (PPIs) with oncoproteins.
- Existing small-molecule inhibitors targeting WDR5 PPIs show limited efficacy in killing cancer cells.
Purpose of the Study:
- To discover and characterize novel WDR5 proteolysis-targeting chimeras (PROTACs) for pancreatic ductal adenocarcinoma (PDAC) treatment.
- To investigate the structure-activity relationships of WDR5 PROTAC degraders.
- To identify key residues involved in WDR5 PROTAC-mediated degradation.
Main Methods:
- Structure-activity relationship studies were conducted in pancreatic ductal adenocarcinoma (PDAC) cells.
- Development and evaluation of von Hippel-Lindau (VHL)-recruiting and cereblon (CRBN)-recruiting WDR5 PROTAC degraders.
- Site-directed mutagenesis was used to identify residues critical for WDR5 degradation.
Main Results:
- Discovery of potent WDR5 PROTAC degraders, including compound 11 (MS132), a VHL-recruiting degrader that inhibited PDAC cell proliferation and was bioavailable in mice.
- Compound 25, a CRBN-recruiting degrader, selectively degraded WDR5 over the CRBN neo-substrate IKZF1.
- Site-directed mutagenesis identified WDR5 K296 as essential for PROTAC-induced WDR5 degradation, while K32 was not involved.
Conclusions:
- Developed a highly effective WDR5 degrader with potential therapeutic applications for pancreatic cancer.
- Identified key molecular determinants for WDR5 PROTAC-mediated degradation.
- Generated valuable tool compounds for further research into WDR5 function and targeted protein degradation.
