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

Chem Pharm Bull (Tokyo). 2018;66(3):251-262. doi: 10.1248/cpb.c17-00784.

Abstract

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.

Keywords: 1,3,5-triazine; anaplastic lymphoma kinase; echinoderm microtubule-associated protein-like 4; non-small cell lung cancer.

MeSH terms

  • Administration, Oral
  • Anaplastic Lymphoma Kinase
  • Animals
  • Binding Sites
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Drug Administration Schedule
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Structure, Tertiary
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry*
  • Sulfones / therapeutic use
  • Transplantation, Heterologous
  • Triazines / chemical synthesis
  • Triazines / chemistry*
  • Triazines / therapeutic use

Substances

  • ASP3026
  • Protein Kinase Inhibitors
  • Sulfones
  • Triazines
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases