Evaluation Of Trk Probes In Models For Dry Eye Disease A. Project Summary In previous work, the PI designed small molecules that resemble turn regions in nerve growth factor (NGF) and in neurotrophin-3 (NT-3), for two reasons. First, ?-turn regions in the neurotrophins seem to be hot-spots for their interactions with the tropomyosin receptor kinase (Trk). Second, whereas neurotrophins activate both the Trk receptors and another receptor called p75, the small molecules should only activate the Trk receptors; this is important because activation of p75 has been associated with induction of apoptosis. In the event, several partial agonists were found, and one of them progress to phase 3 clinical trials (Mimetogen) for treatment of dry eye disease, and its fate as a pharmaceutical has yet to be decided. Most of the compounds prepared in that study, however, were not tested for applications in dry eye disease (they were just screened for properties as Trk ligands), and none of them were designed or tested for binding to TrkB (selective receptor for brain derived neurotrophic factor, BDNF). The central hypotheses of this proposal are that: (i) re-synthesis and testing of some of the original hit NGF and NT3 binding-compounds may afford other leads for treatment of dry eye disease; (ii) design principles similar to those used before could be enacted to obtain small molecule ligands that bind TrkB; and, (iii) side-by-side comparison of TrkA, B, and C probes in models for dry eye disease (cellular and in vivo) will reveal the relative impact of these compounds, and, by inference, the relative importance of stimulating those receptors in treatment of dry eye disease.
Evaluation Of Trk Probes In Models For Dry Eye Disease A. Project Narrative Methods used previously in the PI's laboratory will be expanded to prepare and validate small molecules that bind the largely stimulatory tropomyosin receptor kinase (Trk) receptors, but not another receptor (p75) that is associated with cell-death. As a result, a ligand for one of the Trk receptors, ie TrkC, is an advanced clinical candidate for treatment of dry-eye disease, but it progressed to this stage with minimal evaluation of related TrkC ligands in models for dry eye disease, and no evaluation of ligands designed for binding to TrkB. This application is to prepare a panel of Trk-binding ligands and evaluate them using cellular and in vivo models for dry eye disease.
