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

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.

• Authors: 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
• Journal: Oncogene (Oncogene) Vol. 41 Issue 24 Pg. 3328-3340 (06 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35525905 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Ikaros Transcription Factor
• IKZF1 protein, human
• Intracellular Signaling Peptides and Proteins
• Ubiquitin-Protein Ligases
• WDR5 protein, human

Topics

• Humans
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Carcinogenesis
• Ikaros Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors, genetics, metabolism)
• Proteolysis
• Ubiquitin-Protein Ligases (genetics, metabolism)