2. Academic Validation
  3. Discovery of CN-3 as a Next-Generation RET Inhibitor Potently Overcoming Multiple Mutations

Discovery of CN-3 as a Next-Generation RET Inhibitor Potently Overcoming Multiple Mutations

  • J Med Chem. 2026 May 14;69(9):11229-11257. doi: 10.1021/acs.jmedchem.6c00376.
Zi-Xuan Wang 1,  Rui He 2 3,  Min-Hui Chen 1,  Kun Yang 1,  Qian Liu 1,  Jin Yang 1,  Meng-Yuan Zhang 1,  Nuo Qiao 1,  Ming-Dan Zhou 1,  Yan-Cheng Yu 1,  Shan-Liang Sun 1,  Yuan-Hui Lai 3,  Ye Yang 1,  Zhang Zhang 2 3,  Nian-Guang Li 1,  Zhi-Hao Shi 4
Affiliations

Affiliations

  • 1 National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, 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.
  • 3 Department of Thyroid and Breast Surgery, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong 510310, PR China.
  • 4 Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
PMID: 42068291 DOI: 10.1021/acs.jmedchem.6c00376
Abstract

RET fusions and activating mutations drive multiple human cancers, while resistance mutations limit the efficacy of current selective RET inhibitors. Here, we report CN-3, a potent RET Inhibitor active against clinically relevant mutants, including solvent-front (G810R/S/C), gatekeeper (V804M), hinge (Y806H), and catalytic loop (M918T) variants. CN-3 inhibited all tested RET mutants (IC50 < 5 nM) and selectively suppressed proliferation of RET-driven cellular models, including TT (IC50 = 2.48 ± 0.78 nM) and LC-2/ad (IC50 = 17.05 ± 4.90 nM) cells, as well as Ba/F3 cells expressing RET fusions or mutations, without affecting RET-independent or normal cells. Mechanistically, CN-3 blocked RET autophosphorylation and downstream SHC/Akt/ERK signaling, inducing G0-G1 arrest and Apoptosis. In RET-driven xenografts, CN-3 showed dose-dependent antitumor efficacy with good tolerability. Kinase profiling revealed moderate selectivity, with off-target activity mainly restricted to a limited group of Receptor Tyrosine Kinases. These results support CN-3 as a promising lead for next-generation RET-targeted therapies.

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