Design, synthesis, and evaluation of 3,5-disubstituted 7-azaindoles as Trk inhibitors with anticancer and antiangiogenic activities.

Abstract

Tropomyosin-related kinase A (TrkA) is considered a promising target in the development of a therapeutic treatment of cancer and pain. In this study, we designed and synthesized a series of novel 7-azaindole-based Trk kinase inhibitors through the structure-based design strategy. By varying the functional groups at the 3 and 5 positions of a 7-azaindole scaffold, we studied the structure-activity relationships (SAR) profiles and identified a series of potent Trk inhibitors. Representative derivatives showed desirable activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity.

• Authors: Seunghee Hong, Jinhee Kim, Ju Hyeon Seo, Kyung Hee Jung, Soon-Sun Hong, Sungwoo Hong
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 11 Pg. 5337-49 (Jun 14 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22575050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Aza Compounds
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Indoles
• Phosphoinositide-3 Kinase Inhibitors
• Vascular Endothelial Growth Factor A
• Receptor, trkA

Topics

• Angiogenesis Inhibitors (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Aza Compounds (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Gene Expression
• Human Umbilical Vein Endothelial Cells (drug effects, physiology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Indoles (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Phosphoinositide-3 Kinase Inhibitors
• Protein Binding
• Receptor, trkA (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Vascular Endothelial Growth Factor A (metabolism)