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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149616
    PROTAC ERK5 Degrader