Ulecaciclib 是一种具有口服活性的细胞周期蛋白依赖激酶 (CDK) 抑制剂，对CDKs 的ki为 0.62 μM (CDK2/Cyclin A)、0.2 nM (CDK4/Cyclin D1)、3 nM (CDK6/Cyclin D3) 和 0.63 μM (CDK7/Cyclin H)。Ulecaciclib 能够通过血脑屏障，具有良好的药代动力学特性。
| 生物活性 | Ulecaciclib is an orally activitive inhibitor ofcyclin-dependent kinase(CDK), withKivalues 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]. |
| IC50& Target | 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) |
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体外研究
(In Vitro) | Ulecaciclib (compound 2) (40 min) displays inhibitory effect on CDK kinase with Kivalues of 0.62 μM (CDK2/A), 0.2 nM (CDK4/Cyclin D1), 3 nM (CDK6/Cyclin D3), 0.63 μM (CDK7/H), respectively[2].
Ulecaciclib (72 h) exhibits a strong antiproliferative activity against leukemia cells with a growth inhibition GI50value of 10 nM[2].
Ulecaciclib (72 h) inhibits tumor growth with GI50s range from 0.04-5.09 μM and inhibits Ovarian A2780 with an GI50value of 40 nM, in particularly[2].
Cell Viability Assay[2] | Cell Line: | U87, U251, T98G (mycoplasma-free); and MB453, Colo205, H460, A2780, PANC1, LNC, M229 | | Concentration: | 0-10 μM | | Incubation Time: | 72 hours | | Result: | Inhibited cancer cells growth with GI50s of 2.17 μM (U87), 5.09 μM (U251), 4.18 μM (T98G), 0.62 μM (MB453), 1.55 μM (Colo205), 0.41 μM (H460), 0.04 μM (A2780), 1.21 μM (PANC1), 0.28 μM (LNC), 0.83 μM (M229). |
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体内研究
(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 Tmaxof 6.67 h and an half- of 8.34 h, while Cmax=643 ng/mL, AUC(0-24)=9543 ngoh/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)(hong/mL) | AUC(0-∞)(hong/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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | Please store the product under the recommended conditions in the Certificate of Analysis. |
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