Design, Synthesis, and Biological Evaluation of Proteolysis-Targeting Chimeras as Highly Selective and Efficient Degraders of Extracellular Signal-Regulated Kinase 5

被引：4

作者：

Pan, Pengming ^{[1
]}

Geng, Tongtong ^{[1
]}

Li, Zhongtang ^{[1
]}

Ding, Xuyang ^{[1
]}

Shi, Mengyuan ^{[2
]}

Li, Yang ^{[3
]}

Wang, Yashuai ^{[1
]}

Shi, Yuanyuan ^{[1
]}

Wu, Jiaojiao ^{[1
]}

Zhong, Liang ^{[1
]}

Ji, Dengbo ^{[2
]}

Li, Zhongjun ^{[1
]}

Meng, Xiangbao ^{[1
]}

机构：

[1] Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

[2] Peking Univ Canc Hosp & Inst, Minist Educ, Dept Gastrointestinal Surg 3, Key Lab Carcinogenesis & Translat Res, Beijing 100142, Peoples R China

[3] Tianjin Univ Sci & Technol, Coll Biotechnol, China Int Sci & Technol Cooperat Base Food Nutr S, Tianjin 300457, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 19期

基金：

中国国家自然科学基金;

关键词：

ACTIVATED PROTEIN-KINASE; ERK5; INHIBITOR; GROWTH; PHOSPHORYLATION; MELANOMA; ERK1/2; SUPPRESSION; RESISTANCE; LEUCINE;

D O I：

10.1021/acs.jmedchem.3c00864

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Extracellular signal-regulated kinase 5 (ERK5) is recognized as a key member of the mitogen-activated protein kinase family and is involved in tumor growth, migration, and angiogenesis. However, the results of ERK5 inhibition in multiple studies are controversial, and a highly specific ERK5-targeting agent is required to confirm physiological functions. Using proteolysis-targeting chimera technology, we designed the selective ERK5 degrader PPM-3 and examined its biological effect on cancer cells. Interestingly, the selective degradation of ERK5 with PPM-3 did not influence tumor cell growth directly. Based on proteomics analysis, the ERK5 deletion may be associated with tumor immunity. PPM-3 influences tumor development by affecting the differentiation of macrophages. Therefore, PPM-3 is an effective small-molecule tool for studying ERK5 and a promising immunotherapy drug candidate.

引用

页码：13568 / 13586

页数：19

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