Uses
Ulecaciclib is an orally activitive inhibitor of cyclin-dependent kinase (CDK), with Ki values of 0.62 μM (CDK2/Cyclin A), 0.2 nM (CDK4/Cyclin D1), 3 nM (CDK6/Cyclin D3), and 0.63 μM (CDK7/Cyclin H), respectively. Ulecaciclib can cross blood brain barrier and has good pharmacokinetic characteristics[1][2][3].
in vivo
Ulecaciclib (compound 2) (2 mg/kg for i.v.; 10 mg/kg for p.o.) demonstrates a significantly propensity to cross the blood brain barrier in mice, with the brain/plasma ratios are >1.2 (i.v.) or >0.7 (p.o.), respectively[2].
Ulecaciclib (200 mg/kg; p.o.; daily; 21 d) displays in vivo anti-tumour efficacy in mice[2].
Ulecaciclib (25 mg/kg; p.o.; daily; 10 d) demonstrates significant anti-tumour efficacy at lower doses in combination with TMZ (5 mg/kg; p.o.; 5 d/week; 2 weeks) in mice[2].
Ulecaciclib (compound A) (50 mg/kg; p.o.) shows an oral bioavailability of about 21.8%, and good pharmacokinetic profile with Tmax of 6.67 h and an half- of 8.34 h, while Cmax =643 ng/mL, AUC(0-24) =9543 ng?h/mL in male cynomolgus monkeys[3].
Pharmacokinetic of Ulecaciclib in cynomolgus monkeys[3]
| Route | Dose (mg/kg) | T1/2 (h) | Tmax (h) | Cmax (ng/mL) | AUC(0-t) (h?ng/mL) | AUC(0-∞) (h?ng/mL) | Vd (L/kg) | CL (mL/min/kg) | MRT(0-t) (h) | F (%) |
| i.v. | 5 | 6.53 | / | 447 | 4187 | 4560 | 9.79 | 19.4 | 6.64 | / |
| p.o. | 50 | 8.34 | 6.67 | 643 | 9543 | 7305 | / | / | 10.4 | 21.8 |
| Animal Model: | CDl nu/nu female mice (5-6 weeks old; injected with U87 GBM cells, s.c.)[2] |
| Dosage: | 200 mg/kg |
| Administration: | Oral gavage; daily; 21 days |
| Result: | Reduced tumour growth markedly without any overt toxicity.
|
| Animal Model: | GBM orthotopic mouse xenograft models[2] |
| Dosage: | 120 mg/kg |
| Administration: | Oral gavage; daily for 2 days |
| Result: | Inhibited tumor growth on day 21 and increased life span ratio (ILS) of 154.8% for teated mice.
ILS = (DaysT - DaysC)/DaysC, where DaysC = days survived by control group and DaysT = days survived by treatment group.
|
IC 50
cdk2/cyclin A: 0.62 μM (Ki); Cdk4/cyclin D1: 0.2 nM (Ki); cdk6/cyclin D3: 3 nM (Ki); cdk7-cyclin H: 0.63 μM (Ki)
References
[1] International Nonproprietary Names for Pharmaceutical Substances (INN). WHO Drug Information. 2022. 36(2):337.
[2] Wang Shudong, et al. Treatment of proliferative diseases of the CNS using a class of thiazole-pyrimidine compounds that inhibit the activity of CDK4 and/or CDK6[P]. World Intellectual Property Organization, WO2021222967 A1 2021-11-11.
[3] Wang Shudong, et al. Succinate and crystal form thereof as therapeutics[P]. World Intellectual Property Organization, WO2022099357 A1 2022-05-19.
