Identification of cylin-dependent kinase 1 inhibitors of a new chemical type by structure-based design and database searching.
We have selected cyclin-dependent kinase 1 (CDK1), an enzyme participating in the regulation of the cell cycle, as a target in our efforts to discover new antitumor agents. By exploiting available structural information, we designed an ATP-site directed ligand scaffold that allowed us to identify 4-(3-methyl-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-benzenesulfonamide as a new potent inhibitor of CDK1 in a subsequent database search. The synthesis and testing of some analogues confirmed the interest of this class of compounds as novel CDK1 inhibitors.
Furet
P
P
Novartis Pharma Inc., Oncology Research Department, Basel, Switzerland. pascal.furet@pharma.novartis.com
Meyer
T
T
Mittl
P
P
Fretz
H
H
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D042846:CDC2-CDC28 Kinases; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D019992:Databases as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases