Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases.
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.
Braña
Miguel F
MF
Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668-Boadilla del Monte, Madrid, Spain. mfbrana@ceu.es
Cacho
Mónica
M
García
M Luisa
ML
Mayoral
Elena P
EP
López
Berta
B
de Pascual-Teresa
Beatriz
B
Ramos
Ana
A
Acero
Nuria
N
Llinares
Francisco
F
Muñoz-Mingarro
Dolores
D
Lozach
Olivier
O
Meijer
Laurent
L
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
D000970:Antineoplastic Agents; D019926:Cyclin B; D008024:Ligands; D011720:Pyrazoles; D011724:Pyridazines; D000255:Adenosine Triphosphate; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2