Structure-based strategy for development of novel ALK inhibitor and dual inhibitor of G protein-coupled receptor signaling

Abstract

Part 1. 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 non-small 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. In this study, I report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M. The protonation of 4-aminoquinoline core could interrupt the ability the N atom of quinoline to act as a hydrogen bond acceptor

therefore, securing selectivity became a debated clinical challenge. In this study, I proposed dual inhibition of specific mAChR subtype and the subtype receptor kinase to obtain the selectivity of inhibition of cell proliferation signaling.

therefore, the pKa and calculated ionization pH values of relevant pyridine-based core moieties were carefully analyzed. Replacement of amine linkage with ether resulted in single-digit nanomolar range inhibitors. Part 2. Discovery of Fluorescent 3-Heteroarylcoumarin Derivatives as Novel Inhibitors of Anaplastic Lymphoma Kinase Altered expression or hyperactivation of anaplastic lymphoma kinase (ALK) is one of the main oncogenic drivers in non-small cell lung cancer. Using structure-based design and in vitro enzyme assays, I identified 3-heteroarylcoumarin as a new template for the development of novel fluorescent ALK inhibitors. Molecular simulation provided structural insights for the design of 3-heteroarylcoumarin derivatives, which were easily prepared through efficient synthetic approaches including direct C-H cross coupling. Importantly, these coumarin-based ALK inhibitors are suitable for a cell imaging tool (ALK/$IC_{50}$ = 0.51 $\mu M$, $\lambda_{emi}$ = 500 nm, $\phi_F$ = 0.29). Part 3. Studies on Effective Dual Inhibition of mAChR M3 and CK1$\alpha$ to Suppress Active Signaling Pathway of ERK1/2 in Cancer Proliferation Low subtype selectivity of mAChR agents induces serious problems in cancer treatment