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

Shulei Pan; Liting Zhang; Xinling Luo; Jinshan Nan; Wei Yang; Huachao Bin; Yang Li; Qiao Huang; Tianqi Wang; Zhiling Pan; Bo Mu; Falu Wang; Chenyu Tian; Yang Liu; Linli Li; Shengyong Yang

doi:10.1021/acs.jmedchem.1c01597

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. Epub 2022 Jan 26.

Authors

Shulei Pan¹, Liting Zhang¹, Xinling Luo², Jinshan Nan¹, Wei Yang¹, Huachao Bin¹, Yang Li¹, Qiao Huang², Tianqi Wang¹, Zhiling Pan¹, Bo Mu¹, Falu Wang¹, Chenyu Tian², Yang Liu¹, Linli Li², Shengyong Yang¹

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-TrkC^G623R allograft mouse models without exhibiting apparent toxicity. Collectively, 11g could be a promising lead compound for drug discovery targeting Trks and deserves further investigation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Resistance, Neoplasm / drug effects
Half-Life
Humans
Mice
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / pathology
Oxazines / chemistry*
Oxazines / metabolism
Oxazines / pharmacology
Oxazines / therapeutic use
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Rats
Receptor, trkA / antagonists & inhibitors*
Receptor, trkA / genetics
Receptor, trkA / metabolism
Receptor, trkB / antagonists & inhibitors*
Receptor, trkB / genetics
Receptor, trkB / metabolism
Receptor, trkC / antagonists & inhibitors*
Receptor, trkC / genetics
Receptor, trkC / metabolism
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

Antineoplastic Agents
Oxazines
Protein Kinase Inhibitors
Receptor, trkA
Receptor, trkB
Receptor, trkC