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Senexin C exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability. | [Uses]
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[1]. | [in vivo]
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].
| parameters | iv (2.5 mg/kg) | po (100 mg/kg) | | plasma | tumor | plasma | tumor | | C0 (μg/mL) | 503 | | | | | Kel (h-1) | 0.93 | 0.06 | 0.2 | 0.1 | | T1/2 (h) | 0.75 | 12.1 | 3.53 | 7.27 | | Tmax (h) | | 0.58 | 12 | 12 | | Cmax (ng/mL or ng/g) | | 488 | 144 | 5728 | | AUC0-24 h (ng x h/ml or ng x h/g) | 331 | 6408 | 2182 | 88,600 | | F% | | | 16.5% | 34.6% |
Eight-week-old female Balb/c mice ( CT26 tumor mode), 2.5 mg/kg, i.v.(2.5 mg/mL Senexin C solution in 5% dextrose); 100 mg/kg, p.o.(10 mg/mL Senexin C solution in 30% propylene glycol/70% PEG-400 vehicle) [1].
| Animal Model: | eight-week-old female Balb/c mice ( CT26 tumor mode)[1] | | Dosage: | 2.5 mg/kg (10 mL/kg of 2.5 mg/mL Senexin C solution in 5% dextrose), 100 mg/kg (10 mL/kg of 10 mg/mL Senexin C solution in 30% propylene glycol/70% PEG-400 vehicle) | | Administration: | 2.5 mg/kg, i.v.; 100 mg/kg, p.o. | | Result: | Showed good oral bioavailability. |
| Animal Model: | eight-week-old female NSG mice ( AML model)[1] | | Dosage: | 40 mg/kg | | Administration: | p.o.; twice daily, 4 weeks | | Result: | Suppressed the systemic growth of MV4-11 AML with good tolerability. |
| [IC 50]
CDK8/CycC: 3.6 nM (IC50); CDK19/CycC: 2.9 nM (Kd); CDK8/CycC: 1.4 nM (Kd) | [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. DOI:10.1021/acs.jmedchem.1c01951 |
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cjbscvictory
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13348960310 13348960310 |
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https://www.weikeqi-biotech.com/ |
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