Structural highlights
Function
[NTRK3_HUMAN] Receptor for neurotrophin-3 (NT-3). This is a tyrosine-protein kinase receptor. Known substrates for the trk receptors are SHC1, PI-3 kinase, and PLCG1. The different isoforms do not have identical signaling properties.
Publication Abstract from PubMed
A series of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides was designed and synthesized as new tropomyosin receptor kinases (Trks) inhibitors by utilizing a structure-guided optimization strategy. One of the most potent compounds 9o suppressed TrkA/B/C with IC50 values of 2.65, 10.47 and 2.95nM, respectively. The compound dose-dependently inhibited brain-derived neurotrophic factor (BDNF)-mediated TrkB activation and suppressed migration and invasion of SH-SY5Y-TrkB neuroblastoma cells expressing high level of TrkB. Inhibitor 9o also inhibited the proliferation of SH-SY5Y-TrkB cells with an IC50 value of 58nM, which was comparable to that of an US FDA recently approved drug LOXO-101. Compound 9o may serve as a new lead compound for further anti-cancer drug discovery.
Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors.,Cui S, Wang Y, Wang Y, Tang X, Ren X, Zhang L, Xu Y, Zhang Z, Zhang ZM, Lu X, Ding K Eur J Med Chem. 2019 Oct 1;179:470-482. doi: 10.1016/j.ejmech.2019.06.064. Epub, 2019 Jun 25. PMID:31271959[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cui S, Wang Y, Wang Y, Tang X, Ren X, Zhang L, Xu Y, Zhang Z, Zhang ZM, Lu X, Ding K. Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors. Eur J Med Chem. 2019 Oct 1;179:470-482. doi: 10.1016/j.ejmech.2019.06.064. Epub, 2019 Jun 25. PMID:31271959 doi:http://dx.doi.org/10.1016/j.ejmech.2019.06.064
