Zipalertinib is a potent, orally active and pan-mutagen-selective EGFR tyrosine kinase inhibitor with a unique scaffold that matches the ATP binding site of the EGFR hinge region and an IC50 value of 1.1-8.0 nM[1][2].Zipalertinib, also known as TAS6417, inhibits EGFR phosphorylation and downstream molecules in NSCLC cell lines expressing EGFR exon 20 insertions, leading to caspase activation[1].Zipalertinib exhibits potent inhibition of the most common EGFR mutations (exon 19 deletions and L858R), with the strongest inhibitory effect on cells harbouring EGFR-T790M, a 1st/2nd generation TKI resistance mutation. At concentrations of less than 10 μM, Zipalertinib inhibits cell proliferation and EGFR signalling in NSCLC cell lines carrying or not carrying the common T790M EGFR mutation[2].Zipalertinib covalently modifies the recombinant EGFR exon 20 in-frame insertion mutation at residue 797 cysteine to inhibit EGFR signalling, thereby inhibiting growth and inducing apoptosis in NSCLC cells driven by the EGFR exon 20 insertion mutation[1].
Zipalertinib 动物研究
Animal study
In an EGFR exon 20 insertion-driven tumour model, Zipalertinib resulted in sustained tumour regression in vivo at doses of 10-200 mg/kg. TAS6417 inhibited the mutant EGFR in tumours but not the wild-type EGFR in skin tissues. Zipalertinib was shown to be effective at 100 and 200 mg/kg/day and prolonged survival in animals with lung cancer[1].
搜索
