Discovery of N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (ASP3026), a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor

Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK in...

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Veröffentlicht in:	Chemical & pharmaceutical bulletin 2018/03/01, Vol.66(3), pp.251-262
Hauptverfasser:	Iikubo, Kazuhiko, Kondoh, Yutaka, Shimada, Itsuro, Matsuya, Takahiro, Mori, Kenichi, Ueno, Yoko, Okada, Minoru
Format:	Artikel
Sprache:	eng
Schlagworte:	1,3,5-triazine Administration, Oral anaplastic lymphoma kinase Animals Anticancer properties Antitumor activity Binding Sites Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - pathology Cell Line, Tumor Derivatives Drug Administration Schedule Drug Evaluation, Preclinical echinoderm microtubule-associated protein-like 4 Enzyme inhibitors Humans Inhibitors Inhibitory Concentration 50 Kinases Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - pathology Lymphoma Mice Mice, Inbred NOD Mice, SCID Molecular Docking Simulation non-small cell lung cancer Non-small cell lung carcinoma Oral administration Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - therapeutic use Protein Structure, Tertiary Protein-tyrosine kinase Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - metabolism Structure-Activity Relationship Sulfones - chemical synthesis Sulfones - chemistry Sulfones - therapeutic use Therapeutic applications Transplantation, Heterologous Triazine Triazines - chemical synthesis Triazines - chemistry Triazines - therapeutic use Xenografts
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Zusammenfassung:	Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). We synthesized a series of 1,3,5-triazine derivatives and identified ASP3026 (14a) as a potent and selective ALK inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, once-daily oral administration of 14a demonstrated dose-dependent antitumor activity. Here, syntheses and structure–activity relationship (SAR) studies of 1,3,5-triazine derivatives are described.
ISSN:	0009-2363 1347-5223
DOI:	10.1248/cpb.c17-00784