ALK, known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), is an enzyme that in humans is encoded by the ALK gene. It plays a pivotal role in cellular communication and in the normal development and function of the nervous system. In vitro, Brigatinib is a ALK tyrosine kinase receptor inhibitor with IC50 values of 0.62nM in H3122 human non-small-cell lung cancer cells (measured by ATP assay) [6], 10 and 24 nM in Ba/F3 cells (expressing either native or mutant EML4-ALK , respectively) [6], 2.00 - 10.2 nM in PC12 rat pheochromocytoma cells with different ALK mutations [7]. Brigatinib was highly active against both sensitive and resistant H3122 cells, decreasing cell growth, suppressing ALK phosphorylation, and inducing apoptosis in 300 nM. In PC12 cells, Brigatinib inhibited and abolished ALK phosphorylation in a dose-dependent manner at concentration ranging from 50 to150 nM, suggesting its inhibition on ALK activity and abrogating proliferation of ALK addicted neuroblastoma cell lines; it also effectively abrogated neurite outgrowth of all tested ALK mutants at both 15 and 30 nM, including ALK-G1269A, ALK-R1275 and ALK-R1192P, suggesting its constitutive inhibition on active ALK mutants and neurite outgrowth. In vivo,dose-dependent antitumor activities were discovered both in a Karpass-299 xenograft mouse model( expressing the NPM−ALK fusion) orally administered with Brigatinib (10mg/kg, 25mg/kg, 50mg/kg) once daily for 13 consecutive days and a NSCLC mouse model (H3122 cells expressing the EML4−ALK fusion) for 19 consecutive days.; it is noticeable that it resulted in tumor regression with no signs of overt toxicity at a dose of 50mg/kg in Karpas-299 xenograft mouse model and tumor regressions at all doses tested (including the lowest 10 mg/kg dose) in a NSCLC mouse model[8]. A retrospective multicentric study showed that Brigatinib exhibited clinical activity in ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. [9].
作用机制
Brigatinib binds to and inhibits ALK kinase and ALK fusion proteins, which leads to the inhibition of ALK phosphorylation, thereby disrupting their signaling pathways and eventually inhibiting tumor cell growth in susceptible tumor cells[10].
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