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Ref Type Journal Article
PMID (24386191)
Authors Narayanan R, Yepuru M, Coss CC, Wu Z, Bauler MN, Barrett CM, Mohler ML, Wang Y, Kim J, Snyder LM, He Y, Levy N, Miller DD, Dalton JT
Title Discovery and preclinical characterization of novel small molecule TRK and ROS1 tyrosine kinase inhibitors for the treatment of cancer and inflammation.
Journal Vol Issue Date Pages Journal Short Title
PloS one 8 12 2013 e83380 PLoS One
URL
Abstract Text 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 NFκB, 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
GTx-186 GTx-186 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
GTx-186 ALK Inhibitor 34 RET Inhibitor 54 ROS1 Inhibitor 23 Trk Receptor Inhibitor (Pan) 33 GTx-186 is a multi-kinase inhibitor targeting TRKA/B/C, ROS1 fusions, ALK, and RET, potentially resulting in decreased growth of ROS1 and TRKA over expressing tumors (PMID: 24386191).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NTRK1 over exp neuroblastoma sensitive GTx-186 Preclinical - Cell line xenograft Actionable In a preclinical study, GTx-186 inhibited Erk signaling, resulted in growth inhibition of neuroblastoma cells overexpressing Ntrk1 in culture and in cell line xenograft models (PMID: 24386191). 24386191