Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies

• 成果类型: Article
• 署名作者: Meyer, Christian T.; Smith, Brianna N.; Wang, Jing; Teuscher, Kevin B.; Grieb, Brian C.; Howard, Gregory C.; Silver, Alexander J.; Lorey, Shelly L.; Stott, Gordon M.; Moore, William J.; Lee, Taekyu; Savona, Michael R.; Weissmiller, April M.; Liu, Qi; Quaranta, Vito; Fesik, Stephen W.; Tansey, William P.
• 署名单位: University of Colorado System; University of Colorado Boulder; Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Middle Tennessee State University; Vanderbilt University; Vanderbilt University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12794
• DOI: 10.1073/pnas.2408889121
• 发表日期: 2024-08-27
• 关键词: cancer; p53; venetoclax; resistance; apoptosis; aml

摘要

WD40 Repeat Domain 5 (WDR5) is a highly conserved nuclear protein that recruits MYC oncoprotein transcription factors to chromatin to stimulate ribosomal protein gene expression. WDR5 is tethered to chromatin via an arginine- binding cavity known as the WIN site. Multiple pharmacological inhibitors of the WDR5- interaction site of WDR5 (WINi) have been described, including those with picomolar affinity and oral bioavailability in mice. Thus far, however, WINi have only been shown to be effective against a number of rare cancer types retaining wild- type p53. To explore the full potential of WINi for cancer therapy, we systematically profiled WINi across a panel of cancer cells, alone and in combination with other agents. We report that WINi are unexpectedly active against cells derived from both solid and blood- borne cancers, including those with mutant p53. Among hematologic malignancies, we find that WINi are effective as a single agent against leukemia and diffuse large B cell lymphoma xenograft models, and can be combined with the approved drug venetoclax to suppress disseminated acute myeloid leukemia in vivo. These studies reveal actionable strategies for the application of WINi to treat blood- borne cancers and forecast expanded utility of WINi against other cancer types.