7XAF

The crystal structure of TrkA kinase in complex with 4^6,14-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxa-11,14-diaza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclo- tetradecaphan-2-yne-45-carboxamide

Summary for 7XAF

• Entry DOI: 10.2210/pdb7xaf/pdb
• Descriptor: High affinity nerve growth factor receptor, 4^6,14-dimethyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-10-oxo-5-oxa-11,14-diaza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclo-tetradecaphan-2-yne-45-carboxamide (2 entities in total)
• Functional Keywords: trka, transferase inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34577.83

Authors

Zhang, Z.M.,Wang, Y.J. (deposition date: 2022-03-17, release date: 2022-06-01, Last modification date: 2023-11-29)

Primary citation

Wang, Z.,Wang, J.,Wang, Y.,Xiang, S.,Song, X.,Tu, Z.,Zhou, Y.,Zhang, Z.M.,Zhang, Z.,Ding, K.,Lu, X.
Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance.
J.Med.Chem., 65:6325-6337, 2022

PubMed Abstract: Tropomyosin receptor kinase (TRK) secondary mutations mediating acquired resistance, especially at the solvent-front (SF) and the DFG motif, represent an unmet clinical need. Small-molecule macrocyclic kinase inhibitors have displayed significant advantages in overcoming clinical resistance driven by kinase mutations; however, all reported small-molecule macrocyclic TRK inhibitors are all type I inhibitors and are therefore much more sensitive to SF than xDFG mutations. Novel therapeutics for patients with xDFG resistance mutations are urgently needed. We report the first highly selective macrocycle-based potent type II TRK inhibitor, , that exhibits high inhibitory potency toward various TRK fusion protein variants as well as wild type. exhibited potent antiproliferative activity against Ba/F3 cells harboring CD74-TRKA and ETV6-TRKC with half-maximum inhibitory concentration (IC) values of 6 and 1.7 nM, respectively. More importantly, also showed potent antiproliferative activity against a panel of SF mutants (IC = 5.6-110 nM) and displayed extraordinary kinome selectivity.

PubMed: 35426680
DOI: 10.1021/acs.jmedchem.2c00308

Experimental method

X-RAY DIFFRACTION (3.00118200625 Å)