AT7519

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].

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.

A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.[Pubmed:25393368]

Br J Cancer. 2014 Dec 9;111(12):2262-7.

BACKGROUND: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks. METHODS: Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients. RESULTS: Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment. CONCLUSIONS: AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.

The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome.[Pubmed:27965411]

Thorax. 2017 Feb;72(2):182-185.

Acute respiratory distress syndrome (ARDS) is a neutrophil-dominant disorder with no effective pharmacological therapies. While the cyclin-dependent kinase inhibitor AT7519 induces neutrophil apoptosis to promote inflammation resolution in preclinical models of lung inflammation, its potential efficacy in ARDS has not been examined. Untreated peripheral blood sepsis-related ARDS neutrophils demonstrated prolonged survival after 20 hours in vitro culture. AT7519 was able to override this phenotype to induce apoptosis in ARDS neutrophils with reduced expression of the pro-survival protein Mcl-1. We demonstrate the first pharmacological compound to induce neutrophil apoptosis in sepsis-related ARDS, highlighting cyclin-dependent kinase inhibitors as potential novel therapeutic agents.

Liquid chromatography-tandem mass spectrometric assay for the cyclin-dependent kinase inhibitor AT7519 in mouse plasma.[Pubmed:24080524]

J Pharm Biomed Anal. 2014 Jan;88:216-20.

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for the cyclin-dependent kinase inhibitor AT7519 in mouse plasma was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing rucaparib as internal standard. After dilution with water, the extract was directly injected into the reversed-phase LC system. The eluate was transferred into the electrospray interface with positive ionization and the analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was validated in a 5-10,000ng/ml calibration range using double logarithmic calibration, 5ng/ml was the lower limit of quantification. Within day precisions (n=6) were 2.9-5.6%, between day (3 days; n=18) precisions 3.2-7.2%. Accuracies were between 95.9 and 99.0% for the whole calibration range. The drug was stable under all relevant analytical conditions. Finally, the assay was successfully used to determine plasma pharmacokinetics after intraperitoneal administration of AT7519 in mice with neuroblastoma xenografts.

Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.[Pubmed:26202950]

Clin Cancer Res. 2015 Nov 15;21(22):5100-9.

PURPOSE: MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. EXPERIMENTAL DESIGN: Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. RESULTS: AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 mumol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug. CONCLUSIONS: This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification.

AT7519 as a potent inhibitor of CDKs, with IC50s of 210, 47, 100, 13, 170, and <10 nM for CDK1, CDK2, CDK4 to CDK6, and CDK9, respectively.

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