The NGF/TrkA pathway plays a central role in the biology of chronic pain.  The Trk A receptor kinase is a member of a family of Trk receptor kinases that includes Trk B and Trk C.  Activation of the receptor tyrosine kinase TrkA by NGF triggers intracellular signaling cascades and protein expression that increases the sensitivity of nociceptors leading to chronic sensitization and pain.  Inhibition of the NGF/TrkA pathway has been validated clinically using NGF-neutralizing monoclonal antibodies that is currently in Phase II-III trials for OA pain.  Using a variety of biophysical techniques, unique HTS hits were validated and establish as competent lead series with novel binding paradigms.  These leads were further optimized for potency and selectivity resulting in several small molecule pan-Trk inhibitors series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases.  We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing.  This talk describes the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.

Discovery of novel and selective pan-Trk inhibitors for chronic pain

247th National Meeting (2014)

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