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.
基金：
National Natural Science Foundation of China [82173666, 82003580]; Guangdong Basic and Applied Basic Research Foundation [2024A1515012317, 2021A1515110211]; Shenzhen Science and Technology Program [2021A1515110211, JCYJ20210324094612035, 2022071718149001, JCYJ2023080810 5913028, 20220811110339002]; Medical and Health Science and Technology Plan Project, Shenzhen Longgang District Science and Technology Innovation Bureau [LGKCYLWS2021000 001]; Yunnan Province Expert Workstation Program [202305AF 150139, YSZJGZZ-2021083]
第一作者机构：[1]Shenzhen Univ, Med Sch, Sch Pharmaceut Sci, Guangdong Key Lab Genome Stabil & Human Dis Preven, Shenzhen 518060, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[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
推荐引用方式(GB/T 7714)：
Du Yi,Chen Xiya,Chen Weiji,et al.Design, synthesis and biological evaluation of a novel PAK1 degrader for the treatment of triple negative breast cancer[J].BIOORGANIC & MEDICINAL CHEMISTRY.2024,112:doi:10.1016/j.bmc.2024.117896.
APA：
Du, Yi,Chen, Xiya,Chen, Weiji,Chen, Gang,Cheng, Xiaoling...&Yao, Dahong.(2024).Design, synthesis and biological evaluation of a novel PAK1 degrader for the treatment of triple negative breast cancer.BIOORGANIC & MEDICINAL CHEMISTRY,112,
MLA：
Du, Yi,et al."Design, synthesis and biological evaluation of a novel PAK1 degrader for the treatment of triple negative breast cancer".BIOORGANIC & MEDICINAL CHEMISTRY 112.(2024)
