Roniciclib (BAY 1000394) 是一种可口服的泛细胞周期蛋白依赖性激酶 (CDK) 抑制剂，对 CDK1、CDK2、CDK3、CDK4、CDK7 和 CDK9 的 IC50 为 5-25 nM。
Roniciclib is an orally bioavailable pan-cyclin dependent kinase (CDK) inhibitor, with IC50s of 5-25 nM for CDK1, CDK2, CDK3, CDK4, CDK7 and CDK9.
Roniciclib (BAY 1000394) inhibits the kinase activity of the cell-cycle CDKs CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclinDwith IC50 values of 7, 9, and 11 nM, respectively. The transcriptional CDKs CDK9/cyclin T1 and CDK7/cyclin H/MAT1 are inhibited in a similar range (5 and 25 nM)[1]. Roniciclib potently inhibits the proliferation of various human and murine tumor cell lines with a very balanced profile (mean IC50 on human tumor cells: 16 nM)[2].
Tumor growth is strongly inhibited in a dose-dependent manner with T/C values of 0.19 at the lower dose and of 0.02 (tumor regression) at the higher dose. Furthermore, Roniciclib strongly inhibits growth of HeLa-MaTu tumors that have been grown to a size of approximately 50mm2 before start of treatment (day 8 after inoculation). Treatment with Roniciclib at doses of 1.5 and 1 mg/kg slow tumor growth to T/C values of 0.15 and 0.62, respectively. Addition of Roniciclib to cisplatin result in a strong tumor growth inhibition with T/C values of 0.01 (1.0 mg/kg Roniciclib) and -0.02 (1.5 mg/kg Roniciclib)[1]. Roniciclib has low blood clearance rates in mouse, rat, and dog (0.51, 0.78, and 0.50 Lh-1kg-1, respectively) [2].
[1]. Siemeister G, et al. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012 Oct;11(10):2265-73. [2]. Lücking U, et al. The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer. ChemMedChem. 2013 Jul;8(7):1067-85.
Animal experiment: | Mice[1]Athymic mice bearing established HeLa-MaTu xenograft tumors of approx. 25 mm2 in size are treated orally with Roniciclib (BAY 1000394) at doses of 0.5, 1.0, 1.5, and 2.0 mg/kg once daily for 21 days. Treatment is well tolerated as no body weight loss below the initial body weight is observed. Additional groups of mice are treated on a cyclic intermittent dosing schedule at doses of 1.5, 2.0, and 2.5 mg/kg twice daily for 2 days followed by 5 days without treatment (2 on/5 off). In total, 3 treatment cycles are completed[1]. |
参考文献: [1]. Siemeister G, et al. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol Cancer Ther. 2012 Oct;11(10):2265-73. | |
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