用于治疗三阴性乳腺癌的新型 PAK1 降解剂的设计、合成和生物学评价

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic & Medicinal Chemistry Pub Date : 2024-08-27 DOI:10.1016/j.bmc.2024.117896

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引用次数: 0

摘要

三阴性乳腺癌是临床上恶性程度最高的亚型之一，迫切需要找到新的治疗方法。p21激活激酶I（PAK1）一直被认为是TNBC的一个有吸引力的治疗靶点。在这项研究中，我们通过将 VHL 或 CRBN 连接酶配体与 PAK1 抑制剂共轭，设计并合成了一系列新型 PROTAC PAK1 降解剂，这些配体由烷基链或 PEG 链连接。其中最有前景的化合物 19s 能在低至 0.1 μM 的浓度下显著降解 PAK1 蛋白，并在 MDA-MB-231 细胞中发挥强效抗增殖活性，IC50 值为 1.27 μM。此外，19s 还在体外表现出强大的抗迁移活性，并在体内诱导肿瘤快速消退。总之，这些研究结果证明 19s 是一种有效的新型 PAK1 降解剂，有望用于 TNBC 治疗。

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Design, synthesis and biological evaluation of a novel PAK1 degrader for the treatment of triple negative breast cancer

Triple-negative breast cancer is one of the most malignant subtypes in clinical practice, and it is urgent to find new therapies. The p21-activated kinase I (PAK1) has been considered to be an attractive therapeutic target for TNBC. In this study, we designed and synthesized a series of novel PROTAC PAK1 degraders by conjugating VHL or CRBN ligase ligands to PAK1 inhibitors which are connected by alkyl chains or PEG chains. The most promising compound, 19s, can significantly degrade PAK1 protein at concentrations as low as 0.1 μM, and achieves potent anti-proliferative activity with an IC₅₀ value of 1.27 μM in MDA-MB-231 cells. Additionally, 19s exhibits potent anti-migration activity in vitro and induces rapid tumor regression in vivo. Collectively, these findings document that 19s is a potent and novel PAK1 degrader with promising potential for TNBC treatment.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.