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.

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.

• Authors: Paul G Wyatt, Andrew J Woodhead, Valerio Berdini, John A Boulstridge, Maria G Carr, David M Cross, Deborah J Davis, Lindsay A Devine, Theresa R Early, Ruth E Feltell, E Jonathan Lewis, Rachel L McMenamin, Eva F Navarro, Michael A O'Brien, Marc O'Reilly, Matthias Reule, Gordon Saxty, Lisa C A Seavers, Donna-Michelle Smith, Matt S Squires, Gary Trewartha, Margaret T Walker, Alison J-A Woolford
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 16 Pg. 4986-99 (Aug 28 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18656911 (Publication Type: Journal Article)

Chemical References

• 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide
• Antineoplastic Agents
• Enzyme Inhibitors
• Piperidines
• Pyrazoles
• Cyclin-Dependent Kinase 2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy)
• Crystallography, X-Ray
• Cyclin-Dependent Kinase 2 (antagonists & inhibitors)
• Drug Design
• Enzyme Inhibitors (chemical synthesis, pharmacokinetics, therapeutic use)
• Humans
• Mice
• Piperidines (chemical synthesis, pharmacokinetics, therapeutic use)
• Pyrazoles (chemical synthesis, pharmacokinetics, therapeutic use)
• Structure-Activity Relationship