title: Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.
abstract: Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.
authors.affiliation: Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668-Boadilla del Monte, Madrid, Spain. mfbrana@ceu.es
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Braña
authors.forename: Mónica
authors.initials: M
authors.lastname: Cacho
authors.forename: M Luisa
authors.initials: ML
authors.lastname: García
authors.forename: Elena P
authors.initials: EP
authors.lastname: Mayoral
authors.forename: Berta
authors.initials: B
authors.lastname: López
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Pascual-Teresa
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos
authors.forename: Nuria
authors.initials: N
authors.lastname: Acero
authors.forename: Francisco
authors.initials: F
authors.lastname: Llinares
authors.forename: Dolores
authors.initials: D
authors.lastname: Muñoz-Mingarro
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000737:chemistry; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D019926:Cyclin B; D008024:Ligands; D011720:Pyrazoles; D011724:Pyridazines; D000255:Adenosine Triphosphate; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2