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.

Article Details

Citation

Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ

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.

J Med Chem. 2008 Aug 28;51(16):4986-99. doi: 10.1021/jm800382h. Epub 2008 Jul 26.

PubMed ID
18656911 [ View in PubMed
]
Abstract

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Cyclin-dependent kinase 2P24941Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(4E)-N-(4-fluorophenyl)-4-[(phenylcarbonyl)imino]-4H-pyrazole-3-carboxamideCyclin-dependent kinase 2IC 50 (nM)1407.222Details
{[(2,6-difluorophenyl)carbonyl]amino}-N-(4-fluorophenyl)-1H-pyrazole-3-carboxamideCyclin-dependent kinase 2IC 50 (nM)37.222Details
4-(acetylamino)-N-(4-fluorophenyl)-1H-pyrazole-3-carboxamideCyclin-dependent kinase 2IC 50 (nM)8507.222Details
4-[(6-chloropyrazin-2-yl)amino]benzenesulfonamideCyclin-dependent kinase 2IC 50 (nM)19007.222Details
4-{[(2,6-difluorophenyl)carbonyl]amino}-N-[(3S)-piperidin-3-yl]-1H-pyrazole-3-carboxamideCyclin-dependent kinase 2IC 50 (nM)447.222Details
5-[(4-AMINOCYCLOHEXYL)AMINO]-7-(PROPAN-2-YLAMINO)PYRAZOLO[1,5-A]PYRIMIDINE-3-CARBONITRILECyclin-dependent kinase 2IC 50 (nM)307.222Details
5-chloro-7-[(1-methylethyl)amino]pyrazolo[1,5-a]pyrimidine-3-carbonitrileCyclin-dependent kinase 2IC 50 (nM)15007.222Details
5-hydroxynaphthalene-1-sulfonamideCyclin-dependent kinase 2IC 50 (nM)1200007.222Details
AT-7519Cyclin-dependent kinase 2IC 50 (nM)477.222Details
N-(4-sulfamoylphenyl)-1H-indazole-3-carboxamideCyclin-dependent kinase 2IC 50 (nM)6607.222Details
N-phenyl-1H-pyrazole-3-carboxamideCyclin-dependent kinase 2IC 50 (nM)970007.222Details
SeliciclibCyclin-dependent kinase 2IC 50 (nM)3707.222Details