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Ref Type Journal Article
PMID (35421578)
Authors Liu X, Zhang L, Wan H, Zhu Z, Jin J, Qin Y, Mao W, Yan K, Fang D, Jiang W, Hu L, Chen J, Chen K, Chen S, Li J, Zhao S, Zheng S, Zhang L, Ding CZ
Title Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations.
Journal Vol Issue Date Pages Journal Short Title
Bioorganic & medicinal chemistry letters 66 2022 Apr 11 128730 Bioorg Med Chem Lett
URL
Abstract Text ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

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