Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6 H-pyrimido[5,4- b][1,4]oxazin-7(8 H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

  • J Med Chem. 2022 Feb 10;65(3):2035-2058. doi: 10.1021/acs.jmedchem.1c01597.
Shulei Pan  1 ,  Liting Zhang  1 ,  Xinling Luo  2 ,  Jinshan Nan  1 ,  Wei Yang  1 ,  Huachao Bin  1 ,  Yang Li  1 ,  Qiao Huang  2 ,  Tianqi Wang  1 ,  Zhiling Pan  1 ,  Bo Mu  1 ,  Falu Wang  1 ,  Chenyu Tian  2 ,  Yang Liu  1 ,  Linli Li  2 ,  Shengyong Yang  1
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
PMID: 35080890 DOI: 10.1021/acs.jmedchem.1c01597
Abstract

Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are attractive therapeutic targets for multiple cancers. Two first-generation small-molecule Trks inhibitors, larotrectinib and entrectinib, have just been approved to use clinically. However, the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized compound 11g exhibited low nanomolar IC50 values against TrkA, TrkB, and TrkC and various drug-resistant mutants. It also showed good kinase selectivity. 11g displayed excellent in vitro antitumor activity and strongly suppressed Trk-mediated signaling pathways in intact cells. In in vivo studies, compound 11g exhibited good antitumor activity in BaF3-TEL-TrkA and BaF3-TEL-TrkCG623R allograft mouse models without exhibiting apparent toxicity. Collectively, 11g could be a promising lead compound for drug discovery targeting Trks and deserves further investigation.

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