Identification of 4‑Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design

Dysregulation of
anaplastic lymphoma kinase (ALK) has been detected
in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion.
Secondary mutations opposing activity of the first-generation ALK
inhibitor crizotinib came into existence, requiring mutation-targeting
drug discovery for the powerful second-line treatment. In this study,
we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib
resistance to ALK L1196M, discovered by the fragment-growing strategy.
The protonation of 4-aminoquinoline core could interrupt the ability
the N atom of quinoline to act as a hydrogen bond acceptor; therefore,
the pKa and calculated ionization pH values
of relevant pyridine-based core moieties were carefully analyzed.
The replacement of amine linkage with ether resulted in single-digit
nanomolar range inhibitors. The inhibitors exhibited significant antiproliferative
effects on H2228 CR crizotinib-resistant cells by decreasing PI3K/AKT
and MAPK signaling. This work constitutes the first example for systematic
investigation of the effect of ionization pH on activity in this system.