2. Academic Validation
  3. Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations

Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations

  • J Med Chem. 2025 Jan 9;68(1):753-775. doi: 10.1021/acs.jmedchem.4c02692.
Qian Zhang 1,  Yingqi He 2 3,  Danni Rao 4 5,  Rui He 2 3,  Lei Yu 6,  Yaoliang Sun 4,  Yuanhui Lai 7,  Zihan Shi 4 5,  Lijie Peng 2 3,  Zhang Zhang 2 3 7,  Shilin Xu 4 1 8 5
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 3 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 7 Department of Thyroid and Breast Surgery, Guangdong Second Provincial General Hospital, Jinan University, Guangzhou 510310, China.
  • 8 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
PMID: 39731581 DOI: 10.1021/acs.jmedchem.4c02692
Abstract

Rearranged during transfection (RET) kinase is a validated therapeutic target for various cancers characterized by RET alterations. Although two selective RET inhibitors, selpercatinib and pralsetinib, have been approved by the FDA, acquired resistance through solvent-front mutations has been identified rapidly. Developing proteolysis targeting chimera (PROTAC) targeting RET mutations offers a promising strategy to combat drug resistance. Herein, we describe the design, synthesis, and evaluation of a series of RET PROTAC degraders. The representative compound QZ2135 (20) effectively degraded RET kinase and its resistant mutants, such as V804M and G810C/R. It also exhibited superior antiproliferative activity against Ba/F3 cells stably expressing oncogenic fusions of RET with solvent-front mutants, including G810C/R/S, compared to its parental inhibitor. Notably, QZ2135 demonstrated in vivo antitumor efficacy in a Ba/F3-KIF5B-RET-G810C xenograft mouse model. Together, this study provides a potential alternative strategy for overcoming acquired resistance to RET inhibitors mediated by solvent-front mutations.

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