Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors

Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against C...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-05, Vol.23 (9), p.2590-2594
Hauptverfasser:	Huang, Xiaohua, Cheng, Cliff C., Fischmann, Thierry O., Duca, José S., Richards, Matthew, Tadikonda, Praveen K., Reddy, Panduranga Adulla, Zhao, Lianyun, Arshad Siddiqui, M., Parry, David, Davis, Nicole, Seghezzi, Wolfgang, Wiswell, Derek, Shipps, Gerald W.
Format:	Artikel
Sprache:	eng
Schlagworte:	2-Aminothiazole-4-carboxamide adenosine triphosphate Amides - chemical synthesis Amides - chemistry Amides - metabolism Binding Sites Checkpoint Kinase 1 chemistry CHK1 protein kinase Crystallography, X-Ray cyclin-dependent kinase Cyclin-Dependent Kinase 2 - antagonists & inhibitors Cyclin-Dependent Kinase 2 - metabolism Drug Design drugs Hybrid compounds Molecular Docking Simulation Protein Binding Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinases - chemistry Protein Kinases - metabolism Structure-Activity Relationship Structure-based drug design Thiazoles - chemistry topology X-ray diffraction
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Zusammenfassung:	Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a ‘U-shaped’ topology and key interactions with the protein surface at the ATP site is also reported.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.02.108