Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists

Authors: Boltaev U1,2, Meyer Y1, Tolibzoda F1,2, Jacques T1, Gassaway M1,2, Xu Q3, Wagner F3, Zhang YL3, Palmer M3, Holson E3, Sames D4,2.
Publisher/Year: Sci Signal. 2017 Aug 22; 10 (493).
Pub Med ID/Journal ID: PMID: 28831019


Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB-dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose-dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target.