Structure-based strategy for development of novel ALK inhibitor and dual inhibitor of G protein-coupled receptor signaling = 구조 기반 전략을 통한 새로운 역형성 림프종 인산화효소 저해제와 G 단백질 연결 수용체 신호의 이중 저해제 개발에 대한 연구

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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
Hong, Sungwooresearcher홍승우researcher
한국과학기술원 :화학과,
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학위논문(박사) - 한국과학기술원 : 화학과, 2019.2,[ii, 76 p. :]


Anaplastic Lymphoma Kinase▼aG Protein-Coupled Receptor▼aCasein Kinase 1▼aKinase Inhibitor▼aFluorescent Inhibitor▼aStructure-Based Drug Design; 역형성 림프종 인산화 효소▼aG 단백질 연결 수용체▼a카제인 키나아제▼a키나아제 저해제▼a구조 기반 약물 설계

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