8J63

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

8J63 の概要

• エントリーDOI: 10.2210/pdb8j63/pdb
• 分子名称: High affinity nerve growth factor receptor, 4^6-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-11-oxo-5-oxa-10,14-diaza-1(3,6)-imidazo[1,2-b]pyridazina-4(1,3)-benzenacyclotetradecaphan-2-yne-4^5-carboxamide (2 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34563.80

構造登録者

Zhang, Z.M.,Wang, Y.J. (登録日: 2023-04-24, 公開日: 2023-09-20, 最終更新日: 2023-10-11)

主引用文献

Wang, Z.,Wang, J.,Wang, Y.,Xiang, S.,Zhou, H.,Song, S.,Song, X.,Tu, Z.,Zhou, Y.,Ding, K.,Zhang, Z.M.,Zhang, Z.,Lu, X.
Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.
J.Med.Chem., 66:12950-12965, 2023

PubMed Abstract: The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound exhibited excellent potency against wide type TRKA/C, TRKA, TRKA and TRKA with IC values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC values of 1.43-47.56 nM. Moreover, demonstrated ideal antitumor efficacy in both BaF3-- and BaF3- xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

PubMed: 37676745
DOI: 10.1021/acs.jmedchem.3c00899

実験手法

X-RAY DIFFRACTION (3.0005 Å)