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Synthesis and Structure-Activity Relationships of EML4-ALK Inhibitors

飯久保, 一彦 筑波大学 DOI:10.15068/00160629

2020.07.27

概要

Echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) is considered a valid therapeutic target for the treatment of EML4–ALK-positive non-small cell lung cancer (NSCLC). In this study, synthesis and structure–activity relationship (SAR) studies on 1,3,5-triazine derivatives and pyrazine-2-carboxamide derivatives were performed to identify novel EML4–ALK inhibitors.

　In Chapter 1, I describe the synthesis and biological evaluation of 1,3,5-triazine derivatives. I also discuss the detailed SAR studies conducted on each structural component of 1,3,5-triazine derivative compounds using computational modeling. First, substituents at the 6- position of the 1,3,5-triazine ring were examined. SAR studies revealed that unsubstituted compound 12a showed the most potent inhibitory activity against EML4–ALK among all compounds reported. Second, the SAR of the sulfonyl moiety of compound 12a was investigated. These experiments revealed that the 2-isopropylsulfonyl derivative had the most potent inhibitory activity against EML4–ALK among all compounds reported. Third, substituent effects at the methoxy group of compound 12a were examined. These experiments showed that the oxygen atom in the 2-methoxy group was important for the compound’s inhibitory activity. Finally, optimization of the amine moiety revealed that compound 12a exhibited the most promising in vitro profile among all compounds reported. The antitumor activity of compound 12a was evaluated in mice xenografted with NCI-H2228, human NSCLC tumor cells that endogenously express EML4–ALK. Oral administration of compound 12a demonstrated dose-dependent antitumor activity and induced tumor regression.

　In Chapter 2, I describe the synthesis and biological evaluation of pyrazine-2- carboxamide derivatives to identify a more potent EML4–ALK inhibitor with a different chemical structure to that of compound 12a. I also discuss the detailed SAR studies conducted on each structural component of pyrazine-2-carboxamide derivative compounds using computational modeling. First, the substituent effects at the ethyl moiety of compound 30a were examined. SAR studies revealed that the ethyl derivative 30a showed the most potent inhibitory activity against EML4–ALK among all compounds reported. Next, optimization of the 3- (methanesulfonyl)anilino component of compound 30a was performed. The docking model of compound 12a with ALK indicated that the amine moiety of compound 12a extends into the solvent-exposed region located outside the ATP-binding pocket. The docking model of 30a suggested that the 3-(methanesulfonyl)anilino moiety of compound 30a extends into the same region. Consistent with this observation, compound 35 retained inhibitory activity against EML4–ALK compared to that of compound 30a (30a: IC50 = 17 nM, 35: IC50 = 8.9 nM). Replacement of the 2-methoxy group of compound 35 with a 3-methoxy group enhanced the inhibitory activity (37a: IC50 = 0.37 nM). Finally, optimization of the amine moiety led to the discovery of compound 37c. The antitumor activity of compound 37c was evaluated in mice xenografted with 3T3 cells expressing EML4–ALK. Once-daily oral administration of compound 37c at a dose of 10 mg/kg for 5 days demonstrated 62% tumor regression, while compound 12a showed 81% tumor growth inhibition.

　Based on the two abovementioned studies, compounds 12a and 37c were identified as novel EML4–ALK inhibitors. In mice xenografted with 3T3 cells expressing EML4–ALK, the antitumor activity of compound 37c was more potent than that observed for compound 12a.

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