title: Potent and selective Aurora inhibitors identified by the expansion of a novel scaffold for protein kinase inhibition.
abstract: 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.
authors.affiliation: Nerviano Medical Sciences - Oncology, via Pasteur 10, 20014 Nerviano, Milan, Italy. daniele.fancelli@nervianoms.com
authors.forename: Daniele
authors.initials: D
authors.lastname: Fancelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Berta
authors.forename: Simona
authors.initials: S
authors.lastname: Bindi
authors.forename: Alexander
authors.initials: A
authors.lastname: Cameron
authors.forename: Paolo
authors.initials: P
authors.lastname: Cappella
authors.forename: Patrizia
authors.initials: P
authors.lastname: Carpinelli
authors.forename: Cornel
authors.initials: C
authors.lastname: Catana
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giordano
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giorgini
authors.forename: Sergio
authors.initials: S
authors.lastname: Mantegani
authors.forename: Aurelio
authors.initials: A
authors.lastname: Marsiglio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Meroni
authors.forename: Juergen
authors.initials: J
authors.lastname: Moll
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.forename: Fulvia
authors.initials: F
authors.lastname: Roletto
authors.forename: Dino
authors.initials: D
authors.lastname: Severino
authors.forename: Chiara
authors.initials: C
authors.lastname: Soncini
authors.forename: Paola
authors.initials: P
authors.lastname: Storici
authors.forename: Roberto
authors.initials: R
authors.lastname: Tonani
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Anna
authors.initials: A
authors.lastname: Vulpetti
authors.forename: Paola
authors.initials: P
authors.lastname: Vianello
mesh_terms: 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
chemical_list: 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