9IVB

Crystal structure of c-Met kinase domain bound by bozitinib

This is a non-PDB format compatible entry.

Summary for 9IVB

• Entry DOI: 10.2210/pdb9ivb/pdb
• Descriptor: Hepatocyte growth factor receptor, bozitinib (3 entities in total)
• Functional Keywords: c-met, bozitinib, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70533.40

Authors

Lin, H.,Chen, Y.H. (deposition date: 2024-07-23, release date: 2025-01-22, Last modification date: 2025-02-12)

Primary citation

Lin, H.,Qu, L.,Wei, H.,Guo, M.,Chen, X.,Lin, Q.,Zhang, H.,Dai, S.,Chen, Y.
Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer.
Commun Biol, 8:134-134, 2025

PubMed Abstract: Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment of c-Met-amplified gastric cancer. Recently, bozitinib, a highly selective c-Met kinase inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung cancer and secondary glioblastoma. In this study, we investigate the antitumor activity of bozitinib against MET-amplified gastric cancer and elucidate its molecular mechanism. Bozitinib demonstrates a strong effect on MET-amplified gastric cancer cells by blocking the c-Met signaling pathway, leading to the inhibition of cell proliferation and survival, as well as the induction of G0/G1 phase arrest and apoptosis. Structurally, bozitinib is optimally embedded in the ATP pocket of c-Met and firmly binds via an extensive interaction network. In addition, bozitinib efficiently inhibits c-Met resistance-conferring mutations G1163R and Y1230H, although its potency is significantly decreased against the D1228N and Y1230C mutations. Overall, our study reveals the molecular mechanism of bozitinib against c-Met, highlights its ability to overcome acquired resistance mutations, and provides valuable insights into further design and improvement of selective c-Met inhibitors.

PubMed: 39875456
DOI: 10.1038/s42003-025-07490-5

Experimental method

X-RAY DIFFRACTION (2.35 Å)