X-376 is identified as a highly potent and specific inhibitor of the ALK tyrosine kinase (TKI), boasting an IC50 value of 0.61 nM, making it less effective against MET with an IC50 of 0.69 nM. Its anticancer efficacy is pronounced[1].
体内研究
In vivo, X-376 demonstrates notable antitumor activity in H3122 xenograft models, featuring significant bioavailability and moderate half-lives. When administered at 50 mg/kg bid to nude mice with H3122 xenografts, it considerably slows tumor growth compared to control, without affecting mouse weight or showing signs of compound-related toxicity. Further safety assessments in Sprague Dawley (SD) rats, with doses up to 100 mg/kg following 10 days of repeated oral administration, show survival without significant toxicity. The determined no significant toxicity (NST) level for X-376 is at 50 mg/kg, achieving an AUC of 41 μM×hr and a Cmax of 5.04 μM[1].
体外研究
X-376 demonstrates strong inhibitory effects on various cancer cell lines with ALK mutations or fusions. For instance, in H3122 lung cancer cells with EML4-ALK E13;A20 mutations, X-376 shows an IC50 of 77 nM. In H2228 lung cancer cells featuring EML4-ALK E6a/b; A20 mutations, it exhibits an IC50 of 57 nM. Additionally, X-376 is effective against SUDHL-1 lymphoma cells harboring NPM-ALK (IC50: 32 nM) and shows inhibition of SY5Y neuroblastoma cells with ALK F1174L mutations, MKN-45 gastric carcinoma cells dependent on MET, HepG2, and PC-9 lung cancer cells with EGFR exon 19 deletions, showing IC50s of 142 nM, 150 nM, 15.137 μM, and 3.062 μM, respectively[1].
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