ArticleComputational and structural biotechnology journal2023
Structural insight into the macrocyclic inhibitor TPX-0022 of c-Met and c-Src.
Article in Computational and structural biotechnology journal, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 6 citations in OpenAlex.
- A Node-Adaptive Feature Fusion Network for Drug-Target Interaction Prediction Based on Multi-View Graphs.Biomolecules · 2026Article
- Tyrosine-Mediated Static and Dynamic Quenching of a Receptor Tyrosine Kinase Biosensor Reveals Inhibitor Binding Modes and Kinase Conformations.ACS chemical biology · 2025Article
- The expanding role of the receptor tyrosine kinase MET as a therapeutic target in non-small cell lung cancer.Cell reports. Medicine · 2025Review
- Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer.Communications biology · 2025Article
- Recent advances in the treatment of non-small cell lung cancer with MET inhibitors.Frontiers in chemistry · 2024Review
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
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Abstract
c-Met has been an attractive target of prognostic and therapeutic studies in various cancers. TPX-0022 is a macrocyclic inhibitor of c-Met, c-Src and CSF1R kinases and is currently in phase I/II clinical trials in patients with advanced solid tumors harboring MET gene alterations. In this study, we determined the co-crystal structures of the c-Met/TPX-0022 and c-Src/TPX-0022 complexes to help elucidate the binding mechanism. TPX-0022 binds to the ATP pocket of c-Met and c-Src in a local minimum energy conformation and is stabilized by hydrophobic and hydrogen bond interactions. In addition, TPX-0022 exhibited potent activity against the resistance-relevant c-Met L1195F mutant and moderate activity against the c-Met G1163R, F1200I and Y1230H mutants but weak activity against the c-Met D1228N and Y1230C mutants. Overall, our study reveals the structural mechanism underlying the potency and selectivity of TPX-0022 and the ability to overcome acquire resistance mutations and provides insight into the development of selective c-Met macrocyclic inhibitors.
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