Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design
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Shinmee Mah1,2, Jung Hee Park3, Hoi-Yun Jung1,2
1Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 34141, Korea.
Abstract:
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.
Insights
New 4-phenoxyquinoline inhibitors overcome resistance to the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in non-small cell lung cancer (NSCLC). These compounds show significant antiproliferative effects by targeting ALK L1196M mutations.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK) dysregulation, specifically EML4-ALK fusion, drives non-small cell lung cancer (NSCLC) progression.
- Acquired resistance to the first-generation ALK inhibitor crizotinib necessitates the development of novel therapeutic agents targeting resistance mutations like ALK L1196M.
Purpose of the Study:
- To discover and characterize novel 4-phenoxyquinoline-based inhibitors effective against crizotinib-resistant ALK mutations.
- To investigate the impact of ionization state and structural modifications on inhibitor efficacy.
Main Methods:
- Fragment-growing strategy for inhibitor discovery.
- Analysis of pKa and ionization pH of pyridine-based core moieties.
- Assessment of antiproliferative effects on crizotinib-resistant H2228 CR cells.
- Evaluation of downstream signaling pathways including PI3K/AKT and MAPK.
Main Results:
- Identification of potent 4-phenoxyquinoline inhibitors with single-digit nanomolar activity against ALK L1196M.
- Demonstration of significant antiproliferative activity in crizotinib-resistant NSCLC cells.
- Elucidation of the role of ionization state in modulating inhibitor potency.
- Inhibitors effectively reduced PI3K/AKT and MAPK signaling pathways.
Conclusions:
- 4-phenoxyquinoline derivatives represent a promising class of inhibitors overcoming crizotinib resistance in ALK-mutated NSCLC.
- Systematic analysis of ionization pH is crucial for optimizing inhibitor design in this context.
- These findings provide a foundation for developing next-generation ALK inhibitors for NSCLC treatment.
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