Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer,Journal of Medicinal Chemistry

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Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-29 , DOI: 10.1021/acs.jmedchem.3c01521
Xufen Yu _{1,

2} , Dongxu Li _{3,

4} , Jithesh Kottur _{1,

2} , Huen Suk Kim _{1,

2} , Laura E Herring ₅ , Yao Yu _{3,

4,

6,

7,

8} , Ling Xie ₄ , Xiaoping Hu _{1,

2} , Xian Chen ₄ , Ling Cai _{3,

6,

7} , Jing Liu _{1,

2} , Aneel K Aggarwal ₂ , Gang Greg Wang _{3,

4,

5,

6,

7,

8} , Jian Jin _{1,

2}

Affiliation

As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein–protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure–activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including 11 (MS132), a highly potent and selective von Hippel–Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and 25, a cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1. Furthermore, by conducting site-directed mutagenesis studies, we determined that WDR5 K296, but not K32, was involved in the PROTAC-induced WDR5 degradation. Collectively, these studies resulted in a highly effective WDR5 degrader, which could be a potential therapeutic for pancreatic cancer and several potentially useful tool compounds.

中文翻译：

发现靶向嵌合体的强效和选择性 WDR5 蛋白水解作为胰腺癌的潜在治疗方法

作为核心染色质调节支架蛋白，WDR5 介导与其他伙伴癌蛋白的许多蛋白质-蛋白质相互作用（PPI）。然而，阻断这些 PPI 的小分子抑制剂发挥的细胞杀伤作用有限。在这里，我们报道了胰腺导管腺癌（PDAC）细胞中的构效关系研究，这些研究导致发现了几种 WDR5 蛋白水解靶向嵌合体（PROTAC）降解剂，包括 11 （MS132），一种高效且选择性的 von Hippel-Lindau （VHL）募集的 WDR5 降解剂，它在 WDR5 和 VHL 之间显示出正结合协同性，有效抑制 PDAC 细胞的增殖，并且在小鼠和 25 中具有生物利用度，一种大脑（CRBN）募集的 WDR5 降解剂，它在 CRBN 新底物 IKZF1 上选择性降解 WDR5。此外，通过进行定点诱变研究，我们确定 WDR5 K296 而不是 K32 参与 PROTAC 诱导的 WDR5 降解。总的来说，这些研究产生了一种高效的 WDR5 降解剂，这可能是胰腺癌的潜在治疗方法和几种可能有用的工具化合物。

更新日期：2023-11-29

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