title: Identification of pyrazine-based TrkA inhibitors: design, synthesis, evaluation, and computational modeling studies.
abstract: Trk receptors play a key role in the development and maintenance of neuronal networks. Recent evidence suggests that the Trk family, specifically TrkA, is an important driver for tumour growth, inflammatory and neuropathic pain, and chemoresistance. Through a computational screen, a novel Trk active pharmacophore was identified and a series of pyrazine-based inhibitors were developed, which potently inhibited TrkA. Inhibitors displayed the highest activity on TrkA when screened against a small, tyrosine kinase panel and also exhibited a non-linear SAR. Predicted binding modes of the inhibitors were examined, which identified exploitable regions for future development of more advanced inhibitors.
authors: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.
authors: Brendan
authors: B
authors: Frett
authors: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.
authors: Nick
authors: N
authors: McConnell
authors: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.
authors: Yuanxiang
authors: Y
authors: Wang
authors: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA; Drug Discovery Center of Innovation, Chongqing University of Arts and Sciences, Yongchuan, Chongqing, P.R. China, 402160.
authors: Zhigang
authors: Z
authors: Xu
authors: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA.
authors: Andrew
authors: A
authors: Ambrose
authors: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA; The University of Arizona Cancer Center, Tucson, Arizona 85724, USA.
authors: Hong-Yu
authors: HY
authors: Li