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

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

  • Bioorg Med Chem. 2019 Apr 15;27(8):1683-1692. doi: 10.1016/j.bmc.2019.03.018.
Kazuhiko Iikubo 1,  Kazuo Kurosawa 2,  Takahiro Matsuya 2,  Yutaka Kondoh 2,  Akio Kamikawa 2,  Ayako Moritomo 2,  Yoshinori Iwai 3,  Hiroshi Tomiyama 3,  Itsuro Shimada 2
Affiliations

Affiliations

  • 1 Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: kazuhiko.iikubo@astellas.com.
  • 2 Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
  • 3 Research Laboratories, Kotobuki Pharmaceutical Co., Ltd., 198 Kamigomyou Sakaki-Machi, Hanishina-Gun, Nagano 389-0697, Japan.
PMID: 30878193 DOI: 10.1016/j.bmc.2019.03.018
Abstract

Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4-ALK-positive non-small cell lung Cancer (NSCLC). We discovered 12c as a novel and potent EML4-ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4-ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure-activity relationship (SAR) using computational modeling.

Keywords

Anaplastic lymphoma kinase; Docking study; Echinoderm microtubule-associated protein-like 4; Pyrazine-2-carboxamide; Structure–activity relationship.

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