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.
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