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

  • J Med Chem. 2023 Oct 12;66(19):13568-13586. doi: 10.1021/acs.jmedchem.3c00864.
Pengming Pan  1 ,  Tongtong Geng  1 ,  Zhongtang Li  1 ,  Xuyang Ding  1 ,  Mengyuan Shi  2 ,  Yang Li  3 ,  Yashuai Wang  1 ,  Yuanyuan Shi  1 ,  Jiaojiao Wu  1 ,  Liang Zhong  1 ,  Dengbo Ji  2 ,  Zhongjun Li  1 ,  Xiangbao Meng  1
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 3. China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
PMID: 37751283 DOI: 10.1021/acs.jmedchem.3c00864
Abstract

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.

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