In Pursuit of an Allosteric Human Tropomyosin Kinase A (TrkA) Inhibitor for Chronic Pain.

Human β-nerve growth factor (β-NGF) and its associated receptor, human tropomyosin receptor kinase A (TrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located TrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective TrkA allosteric inhibitor, .

Deciphering the Allosteric Binding Mechanism of the Human Tropomyosin Receptor Kinase A ( hTrkA) Inhibitors.

Access to cryptic binding pockets or allosteric sites on a kinase that present themselves when the enzyme is in a specific conformational state offers a paradigm shift in designing the next generation small molecule kinase inhibitors. The current work showcases an extensive and exhaustive array of in vitro biochemical and biophysical tools and techniques deployed along with structural biology efforts of inhibitor-bound kinase complexes to characterize and confirm the cryptic allosteric binding pocket and docking mode of the small molecule actives identified for hTrkA. Specifically, assays were designed and implemented to lock the kinase in a predominantly active or inactive conformation and the effect of the kinase inhibitor probed to understand the hTrkA binding and hTrkB selectivity.