Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway

Kenneth Thress, Terry MacIntyre, Haiyun Wang, Dave Whitston, Zhong Ying Liu, Ethan Hoffmann, Tao Wang, Jeffrey L. Brown, Kevin Webster, Charles Omer, Peter E. Zage, Lizhi Zeng, Patrick A. Zweidler-McKay

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Tropomyosin-related kinases (TrkA, TrkB, and TrkC) are receptor tyrosine kinases that, along with their ligands, the neurotrophins, are involved in neuronal cell growth, development, and survival. The Trk-neurotrophin pathway may also play a role in tumorigenesis through oncogenic fusions, mutations, and autocrine signaling, prompting the development of novel Trk inhibitors as agents for cancer therapy. This report describes the identification of AZ-23, a novel, potent, and selective Trk kinase inhibitor. In vitro studies with AZ-23 showed improved selectivity over previous compounds and inhibition of Trk kinase activity in cells at low nanomolar concentrations. AZ-23 showed in vivo TrkA kinase inhibition and efficacy in mice following oral administration in a TrkA-driven allograft model and significant tumor growth inhibition in a Trk-expressing xenograft model of neuroblastoma. AZ-23 represents a potent and selective Trk kinase inhibitor from a novel series with the potential for use as a treatment for cancer.

Original languageEnglish (US)
Pages (from-to)1818-1827
Number of pages10
JournalMolecular Cancer Therapeutics
Volume8
Issue number7
DOIs
StatePublished - Jul 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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