期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 18, 页码 12427-12444出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01099
关键词
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In this study, chemical modification was employed to improve TRK inhibition and a potent inhibitor was identified.
Kinase fusions involving tropomyosin receptor kinases (TRKs) have been proven to act as strong oncogenic drivers and are therefore recognized as attractive therapeutic targets. We screened an in-house kinase-focused library and identified a promising hit compound with a unique tetracyclic scaffold. Compound 1 showed high TRK selectivity but moderate cell growth inhibitory activity as well as a potential risk of inducing CYP3A4. In this report, chemical modification intended to improve TRK inhibition and avoid CYP3A4 induction enabled us to identify an orally bioavailable, selective, and potent TRK inhibitor 7.
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