1220105-88-3Relevant academic research and scientific papers
Design and synthesis of novel orally selective and type II pan-TRK inhibitors to overcome mutations by property-driven optimization
Chang, Ling,Chen, Ching-Ping,Chen, Chiung-Tong,Chen, Pei-Yi,Chiu, Chun-Hsien,Fan, Chu-Min,Hsieh, Hsing-Pang,Huang, Chen-Lung,Li, Mu-Chun,Lin, Wen-Hsing,Su, Yu-Chieh,Wang, Pei-Chen,Yeh, Teng-Kuang
, (2021)
Rare oncogenic NTRK gene fusions result in uncontrolled TRK signaling leading to various adult and pediatric solid tumors. Based on the architecture of our multi-targeted clinical candidate BPR1K871 (10), we designed and synthesized a series of quinazoline compounds as selective and orally bioavailable type II TRK inhibitors. Property-driven and lead optimization strategies informed by structure-activity relationship studies led to the identification of 39, which showed higher (about 15-fold) selectivity for TRKA over AURA and AURB, as well as potent cellular activity (IC50 = 56.4 nM) against the KM12 human colorectal cancer cell line. 39 also displayed good AUC and oral bioavailability (F = 27%), excellent in vivo efficacy (TGI = 64%) in a KM12 xenograft model, and broad-spectrum anti-TRK mutant potency (IC50 = 3.74–151.4 nM), especially in the double-mutant TRKA enzymatic assays. 39 is therefore proposed for further development as a next-generation, selective, and orally-administered type II TRK inhibitor.
FUSED MULTICYCLIC COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Page/Page column 54, (2010/04/25)
Fused multicyclic compounds of formula (I): wherein R′, R″, X, Y, Z, A, B, C, D, and n are defined herein. Also disclosed are a method for inhibiting protein kinase (e.g., Aurora kinase) activity and a method for treating a protein kinase mediated disorde
