2. Academic Validation
  3. Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic

Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic

  • Oncogene. 2022 Jun;41(24):3328-3340. doi: 10.1038/s41388-022-02340-8.
Dongxu Li # 1 2,  Xufen Yu # 3 4,  Jithesh Kottur 3 4,  Weida Gong 1,  Zhao Zhang 5,  Aaron J Storey 6,  Yi-Hsuan Tsai 1,  Hidetaka Uryu 1 2,  Yudao Shen 3 4,  Stephanie D Byrum 6,  Rick D Edmondson 6,  Samuel G Mackintosh 6,  Ling Cai 1 7,  Zhijie Liu 5,  Aneel K Aggarwal 4,  Alan J Tackett 6,  Jing Liu 3 4,  Jian Jin 8 9,  Gang Greg Wang 10 11 12
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3 Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
  • 6 Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 7 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 8 Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 9 Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 10 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 11 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 12 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • # Contributed equally.
PMID: 35525905 DOI: 10.1038/s41388-022-02340-8
Abstract

WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a Cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing oncogenesis to the WDR5 PPI inhibitor, to MS40's non-PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5 PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-cancer strategy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148829
    WDR5 PROTAC Degrader