Discovery of novel KSP-targeting PROTACs with potent antitumor effects in Vitro and in Vivo

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-16 DOI:10.1016/j.ejmech.2024.117052

Deng-Gao Zhao, JieYing Liu, Zhengxi Su, Wenbo Zou, Qianwei Zhou, Ting Yin, Tan Jiyao, Yan-Yan Ma

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Abstract

Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound 21 was identified as a potent KSP degrader with a DC₅₀ (concentration causing 50% of protein degradation) value of 114.8 nM and a D_max (maximum degradation) of 90% in the HCT-116 cells. Compound 21 showed strong antiproliferative activity against HCT-116 cells with an IC₅₀ values of 10 nM. Mechanistic investigations revealed that 21 causes the cell arrest at the G2/M phase and subsequent cell apoptosis. In addition, 21 demonstrated more significant inhibition of tumor growth in an HCT-116 xenograft model compared to its parent compound 1. Our findings suggest that 21 may become the promising leads for further development.

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发现新型 KSP 靶向 PROTACs，其体外和体内抗肿瘤效果显著

驱动蛋白纺锤体蛋白（KSP）在有丝分裂过程中起着至关重要的作用，因此成为治疗癌症的一个有吸引力的靶点。在此，我们报告了利用蛋白水解-靶向嵌合体（PROTAC）技术设计、合成和评估的第一个 KSP 降解剂系列。化合物 21 被鉴定为一种强效 KSP 降解剂，在 HCT-116 细胞中的 DC50（导致 50%蛋白质降解的浓度）值为 114.8 nM，Dmax（最大降解量）为 90%。化合物 21 对 HCT-116 细胞具有很强的抗增殖活性，其 IC50 值为 10 nM。机理研究表明，21 会导致细胞停滞在 G2/M 期，随后细胞凋亡。我们的研究结果表明，与母体化合物 1 相比，21 在 HCT-116 异种移植模型中对肿瘤生长的抑制作用更为显著。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.