Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, and echinoderm microtubule-associated protein-like 4 (EML4)–ALK oncogenic fusion kinase is currently considered a validated therapeutic target for the treatment of EML4–ALK-positive non-small cell lung cancer (NSCLC). We previously reported ASP3026, a 1,3,5-triazine derivative, as a novel EML4–ALK inhibitor. Our next objective was to prepare another potent EML4–ALK inhibitor with a different chemical structure from that of ASP3026. In-house library screening and subsequent preliminary structure–activity relationship (SAR) exploration identified 1, a pyrazine-2-carboxamide derivative. Structural optimization of 1 led to the discovery of 2 as a novel and potent EML4–ALK inhibitor. Oral administration of 2 demonstrated potent antitumor activity in mice xenografted with 3T3 cells expressing EML4–ALK. The synthesis and biological evaluation of pyrazine-2-carboxamide derivatives will be presented, together with studies on their SAR using computational modeling.

Synthesis and structure–activity relationships of pyrazine-2-carboxamide derivatives as novel echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) inhibitors

2019 Fall National Meeting

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