Discovery, design, and synthesis of indole-based EZH2 inhibitors.
Bioorganic & Medicinal Chemistry Letters(2015)
摘要
The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002μM), cellular potency (EC50=0.080μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model.
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关键词
EZH2,PRC2,Histone methyltransferase,Epigenetics,Pyridone
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