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Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors |
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| Authors: | Xiaohua Huang Cliff C. Cheng Thierry O. Fischmann José S. Duca Matthew Richards Praveen K. Tadikonda Panduranga Adulla Reddy Lianyun Zhao M. Arshad Siddiqui David Parry Nicole Davis Wolfgang Seghezzi Derek Wiswell Gerald W. Shipps |
| Affiliation: | 1. Merck Research Laboratories, 320 Bent Street, Cambridge, MA 02141, United States;2. Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ 07033, United States;3. Merck Research Laboratories, 901 South California Avenue, Palo Alto, CA 94304, United States |
| Abstract: | 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. |
| Keywords: | CHK1 protein kinase 2-Aminothiazole-4-carboxamide Hybrid compounds Structure-based drug design |
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