6KZC

crystal structure of TRKc in complex with 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methyl-N-(3-((4- methylpiperazin-1-yl)methyl)-5- (trifluoromethyl)phenyl)benzamide

Summary for 6KZC

• Entry DOI: 10.2210/pdb6kzc/pdb
• Descriptor: NT-3 growth factor receptor, 3-(2-imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methyl-~{N}-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]benzamide (3 entities in total)
• Functional Keywords: trkc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36345.14

Authors

Zhang, Z.M.,Wang, Y. (deposition date: 2019-09-23, release date: 2019-10-09, Last modification date: 2024-03-27)

Primary citation

Cui, S.,Wang, Y.,Wang, Y.,Tang, X.,Ren, X.,Zhang, L.,Xu, Y.,Zhang, Z.,Zhang, Z.M.,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., 179:470-482, 2019

PubMed Abstract: 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 IC values of 2.65, 10.47 and 2.95 nM, 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 IC value of 58 nM, 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.

PubMed: 31271959
DOI: 10.1016/j.ejmech.2019.06.064

Experimental method

X-RAY DIFFRACTION (2 Å)