3-Amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: a new class of CDK2 inhibitors.
We have recently reported about a new class of Aurora-A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. Here we describe the synthesis and early expansion of CDK2/cyclin A-E inhibitors belonging to the same chemical class. Synthesis of the compounds was accomplished using a solution-phase protocol amenable to rapid parallel expansion. Compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit CDK2-mediated tumor cell proliferation have been obtained.
Pevarello
Paolo
P
Department of Chemistry, Nerviano Medical Science, BU-Oncology, Via Pasteur 10, 20014 Nerviano MI, Italy. paolo.pevarello@nervianoms.com
Fancelli
Daniele
D
Vulpetti
Anna
A
Amici
Raffaella
R
Villa
Manuela
M
Pittalà
Valeria
V
Vianello
Paola
P
Cameron
Alexander
A
Ciomei
Marina
M
Mercurio
Ciro
C
Bischoff
James R
JR
Roletto
Fulvia
F
Varasi
Mario
M
Brasca
Maria Gabriella
MG
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology*; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000037:antagonists & inhibitors; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D019925:Cyclin A; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2