Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer,Journal of Medicinal Chemistry

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Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-06-06 , DOI: 10.1021/acs.jmedchem.3c00505
Yin Sun ₁ , Yanli Xue ₁ , Pengkun Sun ₁ , Shuyi Mu ₁ , Hongbing Liu ₂ , Yu Sun ₁ , Lin Wang ₁ , Jingkai Wang ₁ , Tianxiao Wu ₁ , Wenbo Yin ₁ , Qiaohua Qin ₁ , Yixiang Sun ₁ , Nian Liu ₁ , Hanxun Wang ₁ , Huali Yang ₁ , Dongmei Zhao ₁ , Maosheng Cheng ₁

Affiliation

Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially TRIM37-amplified breast cancer. The development of novel and effective therapeutic strategies for TRIM37-amplified breast cancer therapy is challenging and extremely desirable. Herein, a structure–activity relationship (SAR) study with an emphasis on exploring different linker lengths and compositions was performed to report the discovery and characterization of SP27 as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. SP27 exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the TRIM37-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.

中文翻译：

发现第一个有效的、选择性的、体内有效的 Polo 样激酶 4 蛋白水解靶向嵌合体降解剂，用于治疗 TRIM37 扩增的乳腺癌

Polo 样激酶 4 (PLK4) 是中心粒复制的主要调节因子，已被提议作为多种癌症的治疗靶点，尤其是TRIM37扩增的乳腺癌。TRIM37扩增乳腺癌治疗的新颖且有效的治疗策略的开发具有挑战性且非常令人期待。在此，进行了结构-活性关系（SAR）研究，重点是探索不同的接头长度和组成，以报告 SP27 作为第一个选择性 PLK4 蛋白水解靶向嵌合体（PROTAC）降解剂的发现和表征。SP27在体内表现出有效的PLK4降解、更有效的细胞生长抑制以及更高效的精准治疗效果TRIM37比常规抑制剂 CZS-035 扩增 MCF-7 细胞系。此外，在PK研究中，SP27腹腔给药后显示出149%的生物利用度，并且在体内具有强大的抗肿瘤功效。SP27的发现证明了PLK4 PROTAC的实用性和重要性，为研究PLK4依赖的生物学功能和治疗TRIM37扩增的乳腺癌铺平了道路。

更新日期：2023-06-06

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