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

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

doi:10.1371/journal.pone.0083380

Ramesh Narayanan, Michael L Mohler + Show 12 more

Open Access

https://doi.org/10.1371/journal.pone.0083380

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Journal: PloS one	Publication Date: Dec 26, 2013
Citations: 112	License type: CC BY 4.0

Affiliation: GTx (United States), ChemBridge (United States)

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 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.

Highlights

The receptor tyrosine kinase (RTK) family is comprised of 58 transmembrane proteins that regulate many cell functions including proliferation, migration, and cell cycle progression [1]
We synthesized and preclinically characterized novel RTK inhibitors that potently inhibited a subset of kinases important for the development of cancer and inflammation
The ATP binding pocket is highly conserved between RTKs, especially within the class belonging to the same phylogenetic branch

Summary

Introduction

The receptor tyrosine kinase (RTK) family is comprised of 58 transmembrane proteins that regulate many cell functions including proliferation, migration, and cell cycle progression [1]. Increased expression, activating mutations, fusion rearrangements, or coactivation of these proto-oncogenes promote oncogenic transformation of their respective tissues [2,3]. Due to their functional importance, RTKs have evolved as therapeutic targets for the treatment of cancer, inflammation, pain, neurodegenerative diseases, and others [4]. Tropomyosin-related kinase (TRK) is a family of three RTKs (TRK-A, TRK-B, and TRK-C) regulating several signaling pathways that are important for survival and differentiation of neurons [8,9] In addition to their critical function in neurons, they and their ligands (nerve growth factor (NGF), brain derived growth factor (BDNF), and neurotrophins, respectively) are important for non-neuronal cell growth and survival. While NGF antibodies are in clinical trials for pain, K252a, the only small molecule TRK-A inhibitor in the clinic, is currently under evaluation for the treatment of psoriasis [13,14]

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