Casein Kinase inhibitor A51

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

酪蛋白激酶抑制剂 A51（CKIα 抑制剂 A51）是一种新型泛特异性 CKI（CSNK1）抑制剂（Kd=0.5-20 nM，CKIα Kd=5.3 nM）。

Casein Kinase inhibitor A51 (CKIα inhibitor A51) is a novel pan-specific CKI (CSNK1) inhibitor (Kd=0.5-20 nM, CKIα Kd=5.3 nM) that co-targets the transcriptional kinases CDK7 and CDK9, with hardly inhibition of CDK8, CDK13, CDK11a, CDK11b, and CDK19; target both CDK7 and CDK9 with low nM Kd values; induces leukemia cell apoptosis at <160 nM, in correlation to the capacity to stabilize p53; shows high and selective sensitivity against leukemic CFUs in colony-forming unit (CFU) assay, without effect on normal hematopoietic CFUs; blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, induce apoptosis, abolishes the expression of MYC, MDM2, and the anti-apoptotic oncogene MCL1; demonstrates therapeutic efficacy with preserved hematopoiesis and leukemia cure potential in AML mouse models.

Similar to CKIα depletion, Casein Kinase inhibitor A51 (0.05-3.2 μM; 18 hours) treatment of RKO cells abolished most of the Ser45 phosphorylation signal and the consecutive GSK3 phosphorylation cascade resulting in stabilization of β-catenin. Casein Kinase inhibitor A51 is highly effective in inducing leukemia cell apoptosis at 160 nM or lower, mostly in correlation to their capacity to stabilize p53.Casein Kinase inhibitor A51 (0.08-2 μM; 6.5 hours) abolishes the expression of MYC, MDM2, and the anti-apoptotic oncogene MCL1. Casein Kinase inhibitor A51 induces a marked reduction in mRNA expression of MYC and MDM2, yet upregulates the expression of the Wnt targets AXIN2 and CCND1 (Cyclin D1). ]Cell Viability Assay Cell Line:MV4-11 cells.Concentration:0.08 μM, 0.6 μM, 2 μM Incubation Time:6.5 hours Result:Abolishes the expression of MYC, MDM2, and the anti-apoptotic oncogene MCL1.

Oral treatment is initiated at 8 days (Casein Kinase inhibitor A51; 5 mg/kg/day) after leukemia cell inoculation, at which the percentage of leukemia cells in the BM is more than 1.5% of all cells. all A51-treated mice have normal organ morphology and histology and normal blood counts.Pharmacokinetic studies of the inhibitor Casein Kinase inhibitor A51 at 20 mg/kg reveal rapid oral absorption with a Tmax of 0.5-2 hr, Cmax of 1060 ng/mL, T1/2 of 2.5 hr, and area under the curve (AUC) values of 3680 (ng*hr/mL).

CKIα inhibitor A51

Metabolic Enzyme/Protease

Casein Kinase

Casein Kinase

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2079068-74-7

360.89

C18H25ClN6

>98% (HPLC)

In Vitro:?DMSO : 100 mg/mL (277.10 mM)

CN1C(=C(C=N1)C2=NC(=NC=C2Cl)NC3CCC(CC3)N)CC4CC4

(1r,4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine

(-20℃)

With Ice Pack

≥ 2 years