Expanded Profiling of WD Repeat Domain 5 Inhibitors Reveals Actionable Strategies for the Treatment of Hematologic Malignancies

Details

• Personal Author:
  Fesik SW ; Grieb BC ; Howard GC ; Lee T ; Liu Q ; Lorey SL ; Meyer CT ; Moore WJ ; Quaranta V ; Savona MR ; Silver AJ ; Smith BN ; Stott GM ; Tansey WP ; Teuscher KB ; Wang J ; Weissmiller AM
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Blood Hematologic Tests Neoplasms Occupational Health Safety
• Keywords:
  Author Keywords: WDR5 Blood Cells Cancer Therapy Gene Expression Hematology Lymphoma Malignancy Ribosomes Therapeutic Agents Venetoclax
• ISSN:
  0027-8424
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Colorado ; Maryland ; New York ; OSHA Region 2 ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 8 ; Tennessee
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  1-10
• Volume:
  121
• Issue:
  35
• NIOSHTIC Number:
  nn:20070118
• Citation:
  Proc Natl Acad Sci U.S.A. 2024 Aug; 121(35):1-10
• Contact Point Address:
  Michael R. Savona, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, 2220 Pierce Avenue, PRB 770, Nashville, TN 37232
• Email:
  william.p.tansey@vanderbilt.edu
• Federal Fiscal Year:
  2024
• Performing Organization:
  Albert Einstein College of Medicine, Bronx, New York
• Peer Reviewed:
  True
• Start Date:
  20210701
• Source Full Name:
  Proceedings of the National Academy of Sciences of the United States of America
• End Date:
  20240630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:fe1467592810c3f4db743a0b840fb9bc546b1300fa672ad0fd6e21a4e794c1cb0fd3c1b012143d608e67120f2ef686a452dfe3adbc117d0aedd16943fc7193b3
• Download URL:
  https://stacks.cdc.gov/view/cdc/208403/cdc_208403_DS1.pdf
• File Type:
  [PDF - 5.63 MB ]