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

Dongxu Li, Xufen Yu, Jithesh Kottur, Weida Gong, Zhao Zhang, Aaron J. Storey, Yi Hsuan Tsai, Hidetaka Uryu, Yudao Shen, Stephanie D. Byrum, Rick D. Edmondson, Samuel G. Mackintosh, Ling Cai, Zhijie Liu, Aneel K. Aggarwal, Alan J. Tackett, Jing Liu, Jian Jin, Gang Greg Wang

Producción científica: Articlerevisión exhaustiva

20 Citas (Scopus)


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.

Idioma originalEnglish (US)
Páginas (desde-hasta)3328-3340
Número de páginas13
EstadoPublished - jun 10 2022
Publicado de forma externa

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Cancer Research


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