Development of CDK2 and CDK5 Dual Degrader TMX-2172.,Angewandte Chemie International Edition

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Development of CDK2 and CDK5 Dual Degrader TMX-2172.
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-05-15 , DOI: 10.1002/anie.202004087
Mingxing Teng _{1,

2} , Jie Jiang _{1,

2} , Zhixiang He _{1,

2} , Nicholas P Kwiatkowski _{1,

2} , Katherine A Donovan _{1,

2} , Caitlin E Mills ₃ , Chiara Victor ₃ , John M Hatcher _{1,

2} , Eric S Fischer _{1,

2} , Peter K Sorger ₃ , Tinghu Zhang _{1,

2} , Nathanael S Gray _{1,

2}

Affiliation

Cyclin‐dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of cancer. Development of CDK2 inhibitors has been extremely challenging as its ATP‐binding site shares high similarity with CDK1, a related kinase whose inhibition causes toxic effects. Here, we report the development of TMX‐2172, a heterobifunctional CDK2 degrader with degradation selectivity for CDK2 and CDK5 over not only CDK1, but transcriptional CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well. In addition, we demonstrate that antiproliferative activity in ovarian cancer cells (OVCAR8) depends on CDK2 degradation and correlates with high expression of cyclin E1 (CCNE1), which functions as a regulatory subunit of CDK2. Collectively, our work provides evidence that TMX‐2172 represents a lead for further development and that CDK2 degradation is a potentially valuable therapeutic strategy in ovarian and other cancers that overexpress CCNE1.

中文翻译：

CDK2 和 CDK5 双降解器 TMX-2172 的开发。

细胞周期蛋白依赖性激酶 2 (CDK2) 是治疗癌症的潜在治疗靶点。CDK2 抑制剂的开发极具挑战性，因为其 ATP 结合位点与 CDK1 具有高度相似性，CDK1 是一种相关激酶，其抑制作用会导致毒性作用。在这里，我们报告了 TMX-2172 的开发，这是一种异双功能 CDK2 降解剂，不仅对 CDK1，而且对转录 CDK（CDK7 和 CDK9）和细胞周期 CDK（CDK4 和 CDK6）具有选择性降解 CDK2 和 CDK5。此外，我们证明卵巢癌细胞 (OVCAR8) 的抗增殖活性取决于 CDK2 的降解，并与细胞周期蛋白 E1 (CCNE1) 的高表达相关，细胞周期蛋白 E1 (CCNE1) 是 CDK2 的调节亚基。总的来说，

更新日期：2020-05-15

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