In Pursuit of an Allosteric Human Tropomyosin Kinase A (hTrkA) Inhibitor for Chronic Pain.
Govindan SubramanianBrian DuclosPaul D JohnsonTracey WilliamsJason T RossScott J BowenYaqi ZhuJulie A WhiteCarolyn HedkeDennis HuczekWendy CollardChristopher JavensRajendran VairagoundarTomasz RespondekTheresa ZacharyTodd MadduxMark R CoxSteven KamerlingAndrea J GonzalesPublished in: ACS medicinal chemistry letters (2021)
Human β-nerve growth factor (β-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit β-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.
Keyphrases
- chronic pain
- pain management
- small molecule
- growth factor
- endothelial cells
- induced pluripotent stem cells
- protein kinase
- pluripotent stem cells
- tyrosine kinase
- oxidative stress
- high resolution
- magnetic resonance imaging
- protein protein
- magnetic resonance
- physical activity
- spinal cord injury
- social support
- drug delivery
- peripheral nerve