6PL2

TRK-A IN COMPLEX WITH LIGAND 1a

Summary for 6PL2

• Entry DOI: 10.2210/pdb6pl2/pdb
• Descriptor: High affinity nerve growth factor receptor, N-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-2-{[1-(4-hydroxyphenyl)-1H-tetrazol-5-yl]sulfanyl}acetamide (3 entities in total)
• Functional Keywords: trk-a kinase domain, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35878.25

Authors

Subramanian, G. (deposition date: 2019-06-30, release date: 2019-09-04, Last modification date: 2024-10-16)

Primary citation

Subramanian, G.,Bowen, S.J.,Zhu, Y.,Roush, N.,Zachary, T.,Javens, C.,Williams, T.,Janssen, A.,Gonzales, A.
Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).
Bioorg.Med.Chem.Lett., 29:126624-126624, 2019

PubMed Abstract: In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.

PubMed: 31444087
DOI: 10.1016/j.bmcl.2019.126624

Experimental method

X-RAY DIFFRACTION (2.59 Å)