Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies
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.
Authors
- Vito Quaranta (ORCID: https://orcid.org/0000-0001-7491-8672)
- Stephen W. Fesik (ORCID: https://orcid.org/0000-0001-5957-6192)
- Gregory C. Howard (ORCID: https://orcid.org/0000-0002-8373-4573)
- Alexander J. Silver (ORCID: https://orcid.org/0000-0001-8255-3140)
- Christian T. Meyer (ORCID: https://orcid.org/0000-0002-8719-6522)
- Brian C. Grieb (ORCID: https://orcid.org/0000-0003-3980-8050)
- April M. Weissmiller (ORCID: https://orcid.org/0000-0003-4505-0530)
- Kevin B. Teuscher (ORCID: https://orcid.org/0009-0008-1039-015X)
- Michael Robert Savona (ORCID: https://orcid.org/0000-0003-3763-5504)
- William P. Tansey (ORCID: https://orcid.org/0000-0002-3900-0978)
- Gordon M. Stott (ORCID: https://orcid.org/0000-0002-9148-6100)
- Brianna N. Smith (ORCID: https://orcid.org/0000-0002-6905-9196)
- William Moore (ORCID: https://orcid.org/0000-0002-0929-2228)
- Shelly L. Lorey (ORCID: https://orcid.org/0000-0002-8151-8711)
- Jing Wang (ORCID: https://orcid.org/0000-0002-7566-1212)
- Qi Liu (ORCID: https://orcid.org/0000-0001-8892-7078)
- Taekyu Lee (ORCID: https://orcid.org/0000-0002-1957-427X)
Institutions
- Leidos (United States) (US)
- Middle Tennessee State University (US)
- University of Colorado Boulder (US)
- Vanderbilt University (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1073/pnas.2408889121
- Citations
- 10
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 4.54
Funders
- Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
- TG Therapeutics
- Astex Pharmaceuticals
- Incyte
- National Institutes of Health
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases