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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 |
| Institution: | 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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