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

다국어 초록 (Multilingual Abstract)

<P>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 p<I>K</I><SUB>a</SUB> 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.</P><P><B>Graphic Abstract</B>
<IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2017/jmcmar.2017.60.issue-22/acs.jmedchem.7b01039/production/images/medium/jm-2017-01039t_0016.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm7b01039'>ACS Electronic Supporting Info</A></P>