6PL1

TRK-A IN COMPLEX WITH LIGAND 1B

Summary for 6PL1

• Entry DOI: 10.2210/pdb6pl1/pdb
• Descriptor: High affinity nerve growth factor receptor, N-(5-{[(7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl]sulfanyl}-1,3,4-thiadiazol-2-yl)-N'-[3-(trifluoromethyl)phenyl]urea (3 entities in total)
• Functional Keywords: trk-a kinase domain high affinity nerve growth factor receptor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35921.22

Authors

Subramanian, G. (deposition date: 2019-06-30, release date: 2019-10-09, Last modification date: 2024-10-23)

Primary citation

Subramanian, G.,Zhu, Y.,Bowen, S.J.,Roush, N.,White, J.A.,Huczek, D.,Zachary, T.,Javens, C.,Williams, T.,Janssen, A.,Gonzales, A.
Lead identification and characterization of hTrkA type 2 inhibitors.
Bioorg.Med.Chem.Lett., 29:126680-126680, 2019

PubMed Abstract: Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.

PubMed: 31610943
DOI: 10.1016/j.bmcl.2019.126680

Experimental method

X-RAY DIFFRACTION (2.03 Å)