This talk will describe methods utilised in the identification and optimisation of a series of highly potent and selective pan-Trk kinase inhibitors for the treatment of pain. The NGF Pathway is of interest to the pharmaceutical community, with Anti-NGF mABs (e.g. Tanezumab) showing clinical efficacy against pain end-points. Inhibition of the TrkA kinase receptor represents an additional intervention point on the NGF pathway, and offers the potential of an oral pain therapeutic. Exquisitely selective kinase inhibitors were required to deliver the safety profile necessary for chronic use in pain patients. To this end, the selectivity determinants for ATP-site protein kinase inhibitors were assessed and used to prioritize HTS chemical substrate and subsequent optimization strategies. A combination of SBDD (using information from apo and liganded structures) and 2D QSAR models were used to design and deliver compounds with the desired efficacy and safety profile. A retrospective analysis of binding affinity scores vs. measured TrkA activity will also be shared, with commentary on new methods that could truly enable activity-guided prospective design.

Discovery and optimisation of a series of potent and selective Pan-Trk ligands

250th National Meeting (2015)

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