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WD repeat domain 5 (WDR5) inhibitors: a patent review (2016-present)

Jesse A Coker1,2, Shaun R Stauffer1,2

  • 1Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Expert Opinion on Therapeutic Patents
|December 20, 2024
PubMed
Abstract

Insights

The WDR5 protein is a promising anti-cancer target, particularly for leukemias. This review highlights challenges and recommends advancing WDR5 WIN-site inhibitors into clinical trials for leukemia treatment.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Medicinal Chemistry

Background:

  • WDR5 is an epigenetic scaffolding protein and a key anti-cancer drug target, especially for MLL-rearranged leukemias.
  • The WDR5 WIN-site, crucial for chromatin tethering, has been targeted by potent small-molecule inhibitors.
  • WDR5 degraders and inhibitors targeting the WBM-site have also been developed.

Purpose of the Study:

  • To provide a comprehensive overview of chemical matter targeting WDR5, focusing on underreported proprietary compounds.
  • To identify and address key challenges hindering WDR5-targeted drug development.

Main Methods:

  • International patent literature survey using SciFinder (2016-2024).
  • Analysis of chemical matter targeting WDR5, including WIN-site and WBM-site inhibitors and degraders.

Main Results:

  • Identified a lack of chemical diversity and confusion regarding WIN-site inhibitor mechanisms.
  • Noted a scarcity of brain-penetrant scaffolds and limited pharmacokinetic/pharmacodynamic data.
  • Observed an absence of human safety and efficacy data for WDR5-targeted agents.

Conclusions:

  • Recommends advancing best-in-class WIN-site inhibitors, particularly from the imidazole class, into clinical trials.
  • Suggests focusing clinical testing on leukemia, where WDR5's therapeutic potential is most promising.
  • Emphasizes the need for further research to validate WDR5 as a next-generation therapeutic target.
Keywords:
MLLWBM-siteWDR5WIN-siteWRAD complexleukemia

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