Identification and characterization of the Cucurbitacins, a novel class of small-molecule inhibitors of Tropomyosin receptor kinase a

Abstract

BackgroundNGF-TrkA is well known to play a key role in propagating and sustaining pruritogenic signals, which form the pathology of chronic pruritus. Inhibition of NGF-TrkA is a known strategy for the treatment of pruritus. In the present paper, we describe the identification, in vitro characterization, structure–activity analysis, and inhibitory evaluation of a novel TrkA inhibitory scaffold exemplified by Cucurbitacins (Cus).MethodsCus were identified as TrkA inhibitors in a large-scale kinase library screen. To obtain structural models of Cus as TrkA inhibitors, AutoDock was used to explore their binding to TrkA. Furthermore, PC12 cell culture systems have been used to study the effects of Cus and traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) extracts on the kinase activity of TrkA.ResultsCus block the phosphorylation of TrkA on several tyrosine sites, including Tyr490, Tyr674/675, and Tyr785, and inhibit downstream Akt and MAPK phosphorylation in response to NGF in PC12 cell model systems. Furthermore, traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) containing Cu extracts were shown to inhibit the phosphorylation of TrkA and Akt. These data reveal mechanisms, at least partly, of the anti-pruritus bioactivity of Cus.ConclusionTaken together, with the recent discovery of the important role of TrkA as a therapeutic target, Cus could be the basis for the design of improved TrkA kinase inhibitors, which could someday help treat pruritus.

Emerging Therapeutic Options for Chronic Pruritus

“…Tropomyosin receptor kinase A (TrkA) is a surface transmembrane tyrosine kinase serving as a receptor for NGF and contributes to the development of psoriasis and pruritic response [196]. NGF stimulates histamine secretion from mast cells and sensitization of peripheral sensory nerve terminals.…”

“…Conversely, another study (n = 208) among psoriatic patients reported clinical improvement in terms of psoriatic lesions but no significant reduction of itch when compared with vehicle (4.2 points according to WI-NRS vs. 3.9 points; p = 0.362) [198]. Recently, Zhong et al [196] explored the inhibitory properties against the NGF/TrkA pathway of cucurbitacins, which are tetracyclic triterpenes derived from plants (especially the Cucurbitaceae family). The authors implied cucurbitacins could be potential precursors of successful antipruritics in the future.…”