CDK4/6-IN-15

CDK4/6-IN-15 is an orally active and selective CDK4/6 inhibitor. CDK4/6-IN-15 potently inhibits cancer cells growth. CDK4/6-IN-15 arrests cell cycle at G1 phase and suppresses retinoblastoma tumour suppressor protein (Rb) phosphorylation at S780 and E2 factor (E2F)-regulated gene expression In Vitro CDK4/6-IN-15 (compound 91) (10 μM; 24 h) also potently inhibits FLT3 and MYLK4 with inhibition rates >90%. CDK4/6-IN-15 (0-5 μM; 72 h) suppresses tumour cell proliferation selectively with GI 50 s of 0.107 μM (MV4-11) and 0.325 μM (MDA-MB-453). CDK4/6-IN-15 (0.1-1 μM; 24 h) arrests exclusively the cell cycle at G1 phase in Rb-positive MV4-11 cells and MDA-MB-453 cells. CDK4/6-IN-15 (0.1-1 μM or 0.3-3 μM; 24-96 h) triggers apoptosis in MV4-11 and MDA-MB-453 cells. CDK4/6-IN-15 (0.1-3.3 μM; 4-24 h) inhibits phosphorylation of Rb. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Apoptosis AnalysisCell Line: MV4-11 and MDA-MB-453 cells Concentration: 0.1 μM, 0.5 μM, and 1 μM for MV4-11; 0.3 μM, 0.6 μM, and 3.3 μM for MDA-MB-453 cells Incubation Time: 24 h, 48 h, 72 h, and 96 h Result: Induced cell apoptosis via arresting cell cycle at G1 accompanied with Rb) phosphorylation suppression and E2F-regulated gene expression decreases. Western Blot AnalysisCell Line: MV4-11 (GI 50 =0.107 μM) and MDA-MB-453 (GI 50 =0.325 μM) Concentration: 1×, 5×, 10× GI 50 Incubation Time: 4 h, 12 h, and 24 h Result: Resulted inhibition of Rb phosphorylation at S780. In Vivo CDK4/6-IN-15 (compound 91) (2 mg/kg for i.v. or 10 mg/kg for p.o.; single dose) shows comparable oral absorption in healthy male adult BALB/c mice (20-25 g) as well as (5 mg/kg for i.v. or 200 mg/kg for p.o.; single dose) in male albino Wistar rats (250-350 g) . Pharmacokinetic Analysis Route Dose (mg/kg) CL (mL/min/kg) V ss (L/kg) AUC (μM·h) C max (μM) T max (h) t 1/2 (h) F (%) rat IV 5 155 27.5 1.2 1.4 / 2.1 / PO 20 / / 4.4 0.3 4.3 20.3 95 mouse IV 2 90 15.7 0.7 1.3 / 2.9 / PO 10 / / 4.3 0.6 2.5 2.7 129 MCE has not independently confirmed the accuracy of these methods. They are for reference only. IC50& Target:CDK4 3 nM (IC 50 ) CDK6 0.279 μM (IC 50 ) CDK2 3.335 μM (IC 50 )

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