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

被引：2

作者：

Du, Yi ^{[1
]}

Chen, Xiya ^{[1
,2
]}

Chen, Weiji ^{[1
,2
]}

Chen, Gang ^{[1
,2
]}

Cheng, Xiaoling ^{[1
,2
]}

Wang, Hailing ^{[1
,2
]}

Guo, Ling ^{[3
]}

Li, Chenyang ^{[1
]}

Yao, Dahong ^{[1
,2
]}

机构：

[1] Shenzhen Univ, Med Sch, Sch Pharmaceut Sci, Guangdong Key Lab Genome Stabil & Human Dis Preven, Shenzhen 518060, Peoples R China

[2] Shenzhen Technol Univ, Sch Pharmaceut Sci, Shenzhen 518060, Peoples R China

[3] Kunming Univ Sci & Technol, Dept Sci & Res, Affiliated Anning First Peoples Hosp, Kunming 650302, Yunnan, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2024年 / 112卷

基金：

中国国家自然科学基金;

关键词：

TNBC; PAK1; PROTAC; Degrader; Migration; OPTIMIZATION; INHIBITOR; POTENT;

D O I：

10.1016/j.bmc.2024.117896

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M, and achieves potent anti-proliferative activity with an IC50 value of 1.27 mu M 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.

引用

页数：27

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