2. Academic Validation
  3. Discovery, Optimization, and Evaluation of Novel Pyridin-2(1 H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment

Discovery, Optimization, and Evaluation of Novel Pyridin-2(1 H)-one Analogues as Potent TRK Inhibitors for Cancer Treatment

  • J Med Chem. 2024 Jan 25;67(2):1168-1183. doi: 10.1021/acs.jmedchem.3c01645.
Zichao Xu 1 2 3,  Xia Peng 2,  Renjie Zhang 4 3,  Yinchun Ji 2,  Mengke You 2 3,  Danyi Wang 2 3,  Yanyan Shen 2,  Mingyue Zheng 2 4,  Chunpu Li 2 4 3,  Jing Ai 2 3,  Hong Liu 1 2 4 3
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
PMID: 38227770 DOI: 10.1021/acs.jmedchem.3c01645
Abstract

Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2(1H)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound 14q was identified as a potent Trk Inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.

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