Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation

Ramesh Narayanan, Muralimohan Yepuru, Christopher C. Coss, Zhongzhi Wu, Matthew N. Bauler, Christina M. Barrett, Michael L. Mohler, Yun Wang, Juhyun Kim, Linda M. Snyder, Yali He, Nelson Levy, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammation, pain, neurodegenerative diseases, and other disorders. Activation or over-expression of ALK, ROS1, TRK (A, B, and C), and RET are associated with oncogenic phenotypes of their respective tissues, making them attractive therapeutic targets. Cancer cDNA array studies demonstrated over-expression of TRK-A and ROS1 in a variety of cancers, compared to their respective normal tissue controls. We synthesized a library of small molecules that inhibit the above indicated RTKs with picomolar to nanomolar potency. The lead molecule GTx-186 inhibited RTK-dependent cancer cell and tumor growth. In vitro and in vivo growth of TRK-A-dependent IMR-32 neuroblastoma cells and ROS1-overexpressing NIH3T3 cells were inhibited by GTx-186. GTx-186 also inhibited inflammatory signals mediated by NFkB, AP-1, and TRK-A and potently reduced atopic dermatitis and air-pouch inflammation in mice and rats. Moreover, GTx-186 effectively inhibited ALK phosphorylation and ALK-dependent cancer cell growth. Collectively, the RTK inhibitor GTx-186 has a unique kinase profile with potential to treat cancer, inflammation, and neuropathic pain.

Original languageEnglish (US)
Article number0083380
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Dec 26 2013

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Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
tyrosine
phosphotransferases (kinases)
inflammation
Inflammation
Molecules
neoplasms
receptors
Neoplasms
Growth
pain
Neurodegenerative diseases
Tissue
Small Molecule Libraries
Therapeutics
Phosphorylation
Transcription Factor AP-1
Cell growth
Neuralgia

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation. / Narayanan, Ramesh; Yepuru, Muralimohan; Coss, Christopher C.; Wu, Zhongzhi; Bauler, Matthew N.; Barrett, Christina M.; Mohler, Michael L.; Wang, Yun; Kim, Juhyun; Snyder, Linda M.; He, Yali; Levy, Nelson; Miller, Duane; Dalton, James T.

In: PLoS One, Vol. 8, No. 12, 0083380, 26.12.2013.

Research output: Contribution to journalArticle

Narayanan, Ramesh ; Yepuru, Muralimohan ; Coss, Christopher C. ; Wu, Zhongzhi ; Bauler, Matthew N. ; Barrett, Christina M. ; Mohler, Michael L. ; Wang, Yun ; Kim, Juhyun ; Snyder, Linda M. ; He, Yali ; Levy, Nelson ; Miller, Duane ; Dalton, James T. / Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation. In: PLoS One. 2013 ; Vol. 8, No. 12.
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