Casein Kinase inhibitor A51

• CAT Number: I044382
• CAS Number: 2079068-74-7
• Molecular Formula: C18H25ClN6
• Molecular Weight: 360.88
• Purity: ≥95%
• Synonyms: 4-N-[5-chloro-4-[5-(cyclopropylmethyl)-1-methylpyrazol-4-yl]pyrimidin-2-yl]cyclohexane-1,4-diamine
• InChI: InChI=1S/C18H25ClN6/c1-25-16(8-11-2-3-11)14(9-22-25)17-15(19)10-21-18(24-17)23-13-6-4-12(20)5-7-13/h9-13H,2-8,20H2,1H3,(H,21,23,24)
• InChIKey: RVZJFCNYSSUDCU-UHFFFAOYSA-N
• SMILES: CN1C(=C(C=N1)C2=NC(=NC=C2Cl)NC3CCC(CC3)N)CC4CC4

Casein Kinase inhibitor A51 is a potent and orally active casein kinase 1α (CK1α) inhibitor. Casein Kinase inhibitor A51 induces leukemia cell apoptosis, and has potent anti-leukemic activities[1].
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[1].
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[1].
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)[1].
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[1].
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)[1].

Reference

[1]. Waleed Minzel, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
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