Identification of <i>N</i>-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1<i>H</i>-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design

Wyatt, Paul G.; Woodhead, Andrew J.; Berdini, Valério; Boulstridge, John A.; Carr, Maria G.; Cross, David M.; Davis, Deborah; Devine, Lindsay A.; Early, Theresa R.; Feltell, Ruth E.; Lewis, Edward J.; McMenamin, Rachel; Navarro, Eva F.; O’Brien, M. Alistair; O’Reilly, Marc; Reule, Matthias; Saxty, Gordon; Seavers, Lisa C A; Smith, Donna-Michelle; Squires, M.; Trewartha, Gary; Walker, Margaret T; Woolford, Alison J.-A.

doi:10.1021/jm800382h

Cited by 315 publications

(262 citation statements)

References 50 publications

(108 reference statements)

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“…The inhibition of CDK1 by AT7519 is competitive with ATP, with a K i value of 38 nmol/L (data not shown). This observation is consistent with the X-ray structure of a complex of CDK2 and AT7519, confirming that AT7519 binds within the active site cleft of the enzyme overlapping with the ATPbinding site (31).…”

Section: Resultssupporting

confidence: 86%

“…1A; ref. 31). The inhibitory activity of AT7519 was assayed against several isolated kinases in vitro (Supplementary Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…AT7519 is N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide synthesized by Astex Therapeutics (31).…”

Section: At7519mentioning

confidence: 99%

“…Soaking cocktails of fragments with apo-crystals of CDK2 identified several start points for chemistry. Optimization of one of these start points identified AT7519 as a potent inhibitor of CDKs, which was found to have antitumor activity in animal models of cancer (31). Here, we describe the further biological characterization of AT7519 in models of human cancer in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 95%

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Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

Squires¹,

Feltell²,

Wallis³

et al. 2009

Molecular Cancer Therapeutics

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154

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Cyclin-dependent kinases (CDK), and their regulatory cyclin partners, play a central role in eukaryotic cell growth, division, and death. This key role in cell cycle progression, as well as their deregulation in several human cancers, makes them attractive therapeutic targets in oncology. A series of CDK inhibitors was developed using Astex's fragment-based medicinal chemistry approach, linked to high-throughput X-ray crystallography. A compound from this series, designated AT7519, is currently in early-phase clinical development. We describe here the biological characterization of AT7519, a potent inhibitor of several CDK family members. AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. Tumor regression was observed following twice daily dosing of AT7519 in the HCT116 and HT29 colon cancer xenograft models. We show that these biological effects are linked to inhibition of CDKs in vivo and that AT7519 induces tumor cell apoptosis in these xenograft models. AT7519 has an attractive biological profile for development as a clinical candidate, and the tolerability and efficacy in animal models compare favorably with other CDK inhibitors in clinical development. Studies described here formed the biological rationale for investigating the potential therapeutic benefit of AT7519 in cancer patients. [Mol Cancer Ther 2009;8(2):324 -32]

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Section: Resultssupporting

confidence: 86%

“…1A; ref. 31). The inhibitory activity of AT7519 was assayed against several isolated kinases in vitro (Supplementary Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…AT7519 is N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide synthesized by Astex Therapeutics (31).…”

Section: At7519mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 2 more Smart Citations

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

Squires¹,

Feltell²,

Wallis³

et al. 2009

Molecular Cancer Therapeutics

Self Cite

154

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show abstract

“…SCH 727965 inhibits Cdk1, Cdk2, Cdk5 and Cdk9 activity in vitro in low nanomolar concentrations (IC 50 < 5 nM) and exhibited antiproliferative effects due to complete suppression of Rb phosphorylation and apoptosis induction, respectively. Fragment-based screening techniques identified pyrazole-3-carboxamide AT7519 as potent Cdk2 inhibitor and antiproliferative agent (Wyatt et al, 2008). AT7519 caused cell cycle arrest, growth inhibition, and apoptosis in a large spectrum of human solid tumor cells and colon carcinoma xenograft models (Squires et al, 2009).…”

Section: Overview Of Small Molecule Cdk Inhibitors: Selectivity and Mmentioning

confidence: 99%

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

Graf¹,

Wuest²,

Pietzsch³

2011

Advances in Cancer Therapy

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Kinase Inhibitors: Approved Drugs and Clinical Candidates

Bradbury

2010

Burger's Medicinal Chemistry and Drug Discovery

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During the past two decades, protein kinases involved in a wide range of cellular signaling pathways have proved a tractable class of oncology drug target, and by the end of 2008 nine small‐molecule kinase inhibitors had been approved by regulatory authorities for treatment of human hematological or solid tumors. The majority of protein kinase inhibitors that have progressed to clinical evaluation target the adenosine triphosphate binding site. After a brief overview of design of the pioneering Bcr‐Abl kinase inhibitor imatinib, this chapter is structured around the effect of kinase inhibitor drugs on the “hallmarks of cancer,” the acquired cellular capabilities that collectively promote malignant growth of solid tumors. The chapter continues by reviewing growth factor and antiangiogenic kinase inhibitors, approaches that have now been validated in large‐scale clinical trials, and then proceeds to discuss inhibitors implicated in the cell cycle, survival signaling, and tissue invasion and metastasis. Reviewed in the chapter are approximately 20 oncology kinase drug targets and 60 associated inhibitors with disclosed chemical structures that have been approved by regulatory authorities or are undergoing clinical trials. Synopses of evolution from lead to candidate drug distilled from original articles illustrate themes in kinase inhibitor medicinal chemistry.

show abstract

Identification of N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design

Cited by 315 publications

References 50 publications

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging

Kinase Inhibitors: Approved Drugs and Clinical Candidates

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