Zotiraciclib (SB1317; TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor, emerged with potent CDK (IC50 against CDKs 1, 2 and 9 = 9, 5 and 3 nM, respectively), FLT3 (IC50 = 19 nM) and JAK2 (IC50 = 19 nM) potency.
Zotiraciclib (SB1317; TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor, emerged with potent CDK (IC50 against CDKs 1, 2 and 9 = 9, 5 and 3 nM, respectively), FLT3 (IC50 = 19 nM) and JAK2 (IC50 = 19 nM) potency.
[1] William AD, et al. J Med Chem, 2012, 55(1), 169-196. [2] Goh KC, et al. Leukemia, 2012, 26(2), 236-243. [3] Anthony W, et al. Cancer Res 15 April 2011; 71 (8_Supplement): 3591.
All cell lines are obtained from the American Type Culture Collection and cultured. For proliferation assays in 96-well plates, 20 000 cells are seeded in 100 μL of medium and treated the following day with compounds (e.g., Zotiraciclib) (in triplicate) at concentrations up to 10 μM for 48 h. Cell viability is monitored using the CellTiter-96 Aqueous One solution cell proliferation assay. Dose-response curves are plotted to determine IC50 values for the compounds using the XL-fit software[1].
Mice and Rats[1] Male BALB/c mice (aged ~10-12 weeks and weighing 17-22 g), male Beagle dogs (~6-7 months of age, weighing 10-14 kg), and male Wistar rats (aged 6-8 weeks, weighing 239-249 g) are used in this study. The oral doses for mice, dogs, and rats are 75, 10, and 10 mg/kg, respectively. The doses are administered by gavage as suspensions (0.5% methylcellulose and 0.1% Tween 80) to mice and rats, and as gelatin capsules (12 Torpac) to dogs. Following oral dosing serial blood samples are collected (cardiac puncture in mice, jugular vein in dogs, and superior vena cava in rats) at different time points (0-24 h) in tubes containing K3EDTA as anticoagulant, centrifuged, and plasma is separated and stored at -70°C until analysis. Plasma samples are processed and analyzed by LC-MS/MS. Pharmacokinetic parameters are estimated by noncompartmental methods using WinNonlin.
[1]. William AD, et al. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kina
[2]. Pasha MK, et al. Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42.
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