Doxribtimine CAS# 50-89-5 beta-胸苷

Doxribtimine (JBI-778) shows sub-micromolar inhibitory activity against PRMT5 in biochemical assays (IC50 ~5–15 nM) and potently suppresses PRMT5-dependent symmetric dimethyl-arginine (SDMA) in cell systems (cellular SDMA EC50 typically ~30–100 nM). It inhibits proliferation of PRMT5-addicted cancer cell lines (e.g. MTAP-del) with GI50 values usually in the low hundreds of nM. In vivo, oral dosing in mouse xenograft models (e.g. MTAP-deleted glioma) results in strong target engagement, >80% SDMA reduction in tumor tissue, and tumor growth inhibition of ~60–80% at well-tolerated dose levels (typical efficacious ranges reported ~10–40 mg/kg, once daily or BID). PK is adequate for oral delivery, and tumor exposure exceeds in vitro potency margins. Toxicology in rodents shows the main on-target liabilities of PRMT5 blockade: reversible cytopenias and body weight suppression at high exposures, but an acceptable therapeutic window at efficacious doses.