Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Oncogene. 2022 Jun;41(24):3328-3340. doi: 10.1038/s41388-022-02340-8. Epub 2022 May 7.
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.
WD 重复结构域 5（WDR5）是 MLL/KMT2A 赖氨酸甲基转移酶复合物的一个组成部分，在肿瘤发生中起着至关重要的作用，是一个有吸引力的癌靶点。然而，靶向 WDR5 与其结合伙伴之间蛋白-蛋白相互作用（PPIs）的抑制剂并不能抑制所有 WDR5 介导的致癌功能，并且只发挥了相当有限的抗肿瘤作用。在这里，我们报告了 WDR5 的一个 cereblon（CRBN）募集蛋白水解靶向嵌合体（PROTAC）MS40，它可以选择性地降解 WDR5 和免疫调节药物（IMiDs）的既定新底物：CRBN、Ikaros 锌指（IKZF）转录因子 IKZF1 和 IKZF3。MS40 诱导的 WDR5 降解导致 MLL/KMT2A 复合物从染色质上解离，导致 H3K4me2 减少。转录组分析显示，WDR5 和 IMiDs：CRBN 的靶标都被 MS40 的处理显著抑制。在 MLL 重排的白血病中，IKZF1 高表达和依赖性，MS40 对 WDR5 和 Ikaros 的共同抑制在抑制肿瘤发生方面优于 WDR5 PPI 抑制剂、MS40 的非 PROTAC 对照（MS40N1 和 MS40N2，分别不与 CRBN 和 WDR5 结合），以及匹配的基于 VHL 的 WDR5 PROTAC（MS169，降解 WDR5 但不降解 Ikaros）。MS40 抑制了体外原代白血病患者细胞和体内患者来源异种移植瘤的生长。因此，WDR5 和 Ikaros 的双重降解是一种很有前途的抗癌策略。
