SB1317 是一种有效的细胞周期蛋白依赖性激酶 (CDKs)、Janus 激酶 2 (JAK2) 和 Fms 样酪氨酸激酶-3 (FLT3) 抑制剂。

SB1317 is a potent inhibitor of cyclin dependant kinases (CDKs), Janus kinase 2 (JAK2), and Fms-like tyrosine kinase-3 (FLT3).

SB1317 has a highly novel kinase inhibitory spectrum inhibiting 17 kinases from a panel of 63, 11 of which are CDK/JAK/FLT family members. The others, Lck, Fyn, Fms, TYRO3, ERK5, and p38δ, are implicated in inflammatory and proliferative processes. Human CYP1A2, 3A4, 2C9, and 2C19 isoforms are not inhibited by SB1317 at the highest tested concentration of 25 μM, but SB1317 inhibits CYP2D6 with IC50=0.95 μM, approximately at the plasma Cmax observed at the maximum tolerated dose. SB1317 inhibits cell proliferation concentrations in HCT-116 (IC50=0.079 μM) and HL-60 (IC50=0.059 μM)[1]. SB1317 is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. SB1317 is mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 does not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 does not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro[2].

The recombinant enzymes (CDK2/cyclin A, JAK2, and FLT3) are used. All assays are carried out in 384-well white microtiter plates using the PKLight assay system. This assay platform is a luminometric assay for the detection of ATP in the reaction using a luciferase-coupled reaction. The compounds are tested at eight concentrations prepared from 3- or 4-fold serial dilution starting at 10 μM. For CDK2/cyclin A assay, the reaction mixture consisted of the following components in 25 μL of assay buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 5 mM MnCl2, 5 mM BGP, 1 mM DTT, 0.1 mM sodium orthovanadate), 1.4 μg/mL of CDK2/cyclin A complex, 0.5 μM RbING substrate, and 0.5 μM ATP. The mixture is incubated at room temperature for 2 h. Then 13 μL of PKLight ATP detection reagent is added and the mixture is incubated for 10 min. Luminescence signals are detected on a multilabel plate reader. The analytical software Prism 5.0 is used to generate IC50 values from the data[1].

SB1317 is prepared in DMSO and stored, and then diluted with appropriate medium before use[1]. 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., SB1317 ) (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].

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C23H24N4O

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DMSO:10 mM
Powder: -20°C for 3 years
In solvent: -80°C for 2 years