Uses
AT-7519 is a small-molecule inhibitor of cyclin-dependent kinases (CDK). AT-7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. AT-7519 is being studied for its potential therapeutic benefits in cancer patients.
Definition
ChEBI: 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide is a member of the class of pryrazoles that is 4-amino-1H-pyrazole-3-carboxylic acid in which the primary amino group has been acylated by a 2,6-dichlorobenzoyl group and in which the carboxylic acid has been converted into a carboxamide by formal condensation with the primary amino group of 4-aminopiperidine. It has a role as an EC 2.7.11.22 (cyclin-dependent kinase) inhibitor and an antineoplastic agent. It is a secondary carboxamide, a member of pyrazoles, a dichlorobenzene and a member of piperidines.
Biological Activity
at7519 is a small-molecule inhibitor of cyclin-dependent kinases (cdks) with ic50 values of 210, 47, 100, 13, 170 and <10 nm for cdk1, cdk2, cdk4, cdk5, cdk6 and cdk9, respectively [1].at7519 showed no inhibition activity against cdk3, 7 and other non-cdk kinases. it inhibited cdk1 in an atp- competitive manner with ki value of 38 nm. at7519 potently inhibited the proliferation of various human tumor cell lines and this activity is cell cycle related. at7519 was also effective in cell lines with p53 mutants or suppression, suggesting that the anti-proliferation efficacy is p53-independent. in hct116 cells, 24 h-treatment of at7519 resulted in a remarkable induction of g0-g1 and g2-m cell cycle arrest. besides that, at7519 at concentrations relating to ic50 induced cell apoptosis (24 h) in hct116, a2780 and ht29 cells with 52%, 3% and 94% survival, respectively. moreover, in hct116 tumor-bearing mice, 10 mg/kg at7519 with intraperitoneal injection caused inhibition of npm phosphorylation and induced apoptosis [1, 2].
Enzyme inhibitor
This novel small-molecule multi-CDK inhibitor (FW = 382.24 g/mol; CAS
844442-38-2, 902135-91-5 (HCl), 902135-89-1 (methanesulfonate);
Solubility: 10 mg/mL DMSO; <1 mg/mL Water; Formulation: Dissolved in
0.9% saline), named systematically as 4- (2,6-dichlorobenzamido) -N-
(piperidin-4-yl) -1H-pyrazole-3-carboxamide, targets cyclin dependent
kinases CDK1/cyclin B, CDK2/Cyclin A, CDK3/Cyclin E, CDK4/Cyclin
D1, CDK5/p35 and CDK6/Cyclin D3 with IC50 values of 210 nM, 47 nM,
360 nM, 100 nM, 13 nM and 170 nM, respectively. AT7519 is inactive
against all non-CDK kinases with the exception of GSK3β (IC50 = 89 nM)
. AT7519 displays potent cytotoxicity and apoptosis in multiple
myeloma (MM) models, resulting in vivo tumor growth inhibition and
prolonged survival. AT7519 inhibits CDK-mediated phosphorylation of
RNA polymerase II (RNA pol II), attended by reduced RNA synthesis.
AT7519 inhibits glycogen synthase kinase-3β) phosphorylation, and
pretreatment with a selective GSK-3 inhibitor as well as shRNA GSK-3β
knockdown restores MM survival, suggesting the involvement of GSK-3β
in AT7519-induced apoptosis. GSK-3β activation was independent of RNA
pol II dephosphorylation, as confirmed by a-amanitin, a specific RNA pol
II inhibitor.
References
[1] squires m s, feltell r e, wallis n g, et al. biological characterization of at7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. molecular cancer therapeutics, 2009, 8(2): 324-332.
[2] wyatt p g, woodhead a j, berdini v, et al. identification of n-(4-piperidinyl)-4-(2, 6-dichlorobenzoylamino)-1 h-pyrazole-3-carboxamide (at7519), a novel cyclin dependent kinase inhibitor using fragment-based x-ray crystallography and structure based drug design?. journal of medicinal chemistry, 2008, 51(16): 4986-4999.
