Senexin C is a selective and orally active CDK8/19 inhibitor. Senexin C shows a strong tumor-enrichment pharmacokinetic (PK) profile and tumor-pharmacodynamic (PD) marker responses. Senexin C inhibits the growth of MV4-11 leukemia cells with good tolerability.
Senexin C (compound 20a) exhibits potent CDK8/19 inhibitory activity with high selectivity (IC50s of 56 and 108 nM for 293-NFκB-Luc and MV4-11-Luc cells, respectively)[1].Senexin C (2 µM) shows potency in different kinase assays (IC50= 3.6 nM for CD8/CycC, Kd=1.4 nM for CD8/CycC, Kd=2.9 nM for CDK19/CycC)[1].Senexin C (1 µM, 3 h) shows inhibition on CDK8/19 dependent cellular gene expression[1].
Senexin C (2.5 mg/kg, i.v.; 100 mg/kg, p.o.) shows good oral bioavailability[1].Senexin C (40 mg/kg; p.o.; twice daily for 4 weeks) suppresses the systemic growth of MV4-11 AML with good tolerability[1].Pharmacokinetic Parameters of Senexin C in eight-week-old female Balb/c mice[1].
References:
[1]. Zhang L, et al. A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics. J Med Chem. 2022; 65(4):3420-3433.