Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic PMID: 35525905

ADC Targets in Oncology

2026-04-10

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

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.

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.