trk受体
化学
原肌球蛋白受体激酶A
激酶
药理学
体内
癌症研究
受体
生物化学
生物
神经营养素
生物技术
作者
Zichao Xu,Peng Xia,Renjie Zhang,Yinchun Ji,M. James You,Danyi Wang,Yanyan Shen,Mingyue Zheng,Chunpu Li,Jing Ai,Hong Liu
标识
DOI:10.1021/acs.jmedchem.3c01645
摘要
Tropomyosin receptor kinase (TRK) fusion, an oncogenic form of kinase with pan-tumor occurrence, is a clinically validated important antitumor target. In this study, we screened our in-house kinase inhibitor library against TRK and identified a promising hit compound 4 with a novel pyridin-2(1H)-one scaffold. Through a combination of structure-based drug design and structure-activity relationship (SAR) study, compound 14q was identified as a potent TRK inhibitor with good kinase selectivity. It also blocked cellular TRK signaling, thereby inhibiting TRK-dependent cell viability. Additionally, 14q displayed acceptable pharmacokinetic properties with 37.8% oral bioavailability in mice. Strong in vivo tumor growth inhibition of 14q was observed in subcutaneous M091 and KM12 tumor xenograft models with TRK fusion, causing significant tumor inhibition or even complete tumor regression.
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