Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition.
Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.
Fancelli
Daniele
D
Nerviano Medical Sciences - Oncology, via Pasteur 10, 20014 Nerviano, Milan, Italy. daniele.fancelli@nervianoms.com
Berta
Daniela
D
Bindi
Simona
S
Cameron
Alexander
A
Cappella
Paolo
P
Carpinelli
Patrizia
P
Catana
Cornel
C
Forte
Barbara
B
Giordano
Patrizia
P
Giorgini
Maria Laura
ML
Mantegani
Sergio
S
Marsiglio
Aurelio
A
Meroni
Maurizio
M
Moll
Juergen
J
Pittalà
Valeria
V
Roletto
Fulvia
F
Severino
Dino
D
Soncini
Chiara
C
Storici
Paola
P
Tonani
Roberto
R
Varasi
Mario
M
Vulpetti
Anna
A
Vianello
Paola
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064127:Aurora Kinases; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C500631:N-(2,6-diethylphenyl)-3-(4-(4-methylpiperazin-1-yl)benzoylamino)-4,6-dihydro-1H-pyrrolo(3,4-c)pyrazole-5-carboxamide; D010879:Piperazines; D011758:Pyrroles; D000255:Adenosine Triphosphate; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases