GSK-3685032

GSK-3685032 is a non-time-dependent, noncovalently, first-in-class reversible DNMT1 -selective inhibitor, with an IC 50 of 0.036 μM. GSK-3685032 induces robust loss of DNA methylation, transcriptional activation, and cancer cell growth inhibition In Vitro GSK-3685032 (6 days) has cell growth inhibition of majority cancer cell lines, with a median growth IC 50 value of 0.64 μM. GSK-3685032 (0.1-1000 nM, 1-6 days) exhibits growth inhibition after 3 days, with decreasing growth IC 50 throughout a 6 d time course. GSK3685032 (10-10000 nM, day 4) dose-dependently increases the immune-related gene transcription. GSK3685032 (3.2-10,000 nM, 2 days) inhibits DNMT1 protein expression. GSK3685032 induces DNA hypomethylation and gene activation. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell Line: 15 leukemia, 29 lymphoma and 7 multiple myeloma cell lines, e.g., EOL-1, Ki-JK, MM.IR cells. Concentration: 0.01-100 μM Incubation Time: 6 days Result: Showed cell growth inhibition of majority cancer cell lines, with a median growth IC 50 value of 0.64 μM. Cell Proliferation AssayCell Line: MV4-11 cells Concentration: 0.1-1000 nM Incubation Time: 1-6 days Result: Exhibited growth inhibition after 3 days, with decreasing growth IC 50 throughout a 6 d time course. RT-PCRCell Line: MV4-11 cells Concentration: 10-10000 nM Incubation Time: 4 days Result: Dose-dependent increased of CXCL11, IFI27, HLA-DQA1 and MAGEA4 following treatment of MV4-11 cells. Western Blot AnalysisCell Line: GDM-1 cells Concentration: 3.2-10,000 nM Incubation Time: 2 days Result: Inhibited DNMT1 protein expression In Vivo GSK-3685032 (1-45 mg/kg; subcutaneous twice daily for 28 days) inhibits tumor growth in the subcutaneous MV4-11 or SKM-1 xenograft models . Summary of mouse pharmacokinetic parameters for GSK-3685032 Dose,Route C max (ng/mL) AUC 0-8hr (h*ng/mL) DNAUC (h*kg*ng/mL/mg) Clearance (mL/min/kg) Volume dss (L/kg) T 1/2 (h) 2 mg/kg,IV 5103 2418 1209 13 1.3 1.8 2 mg/kg,SC 252 921 461 NA NA 2.8 2 mg/kg,SC 5473 15400 513 NA NA ND MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: MV4-11 xenograft models (female CD1-Foxn1 mice, 12 weeks of age) or SKM-1 xenograft models (NOD. CB17-Prkdc 1NCrCrl mice, 8-11 weeks of age) Dosage: 1, 5, 15, 30, 45 mg/kg (10% captisol adjusted to pH 4.5-5 with 1 M acetic acid, stored for up to 1 week at 4 °C) Administration: Subcutaneous injection, twice daily for 4 weeks Result: Revealed statistically significant dose-dependent tumor growth inhibition with clear regression at ≥30 mg/kg. Form:Solid IC50& Target:DNMT1

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