title: Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.
abstract: The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
authors: Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano (MI), Italy. gabriella.brasca@nervianoms.com
authors: Maria Gabriella
authors: MG
authors: Brasca
authors: Nadia
authors: N
authors: Amboldi
authors: Dario
authors: D
authors: Ballinari
authors: Alexander
authors: A
authors: Cameron
authors: Elena
authors: E
authors: Casale
authors: Giovanni
authors: G
authors: Cervi
authors: Maristella
authors: M
authors: Colombo
authors: Francesco
authors: F
authors: Colotta
authors: Valter
authors: V
authors: Croci
authors: Roberto
authors: R
authors: D'Alessio
authors: Francesco
authors: F
authors: Fiorentini
authors: Antonella
authors: A
authors: Isacchi
authors: Ciro
authors: C
authors: Mercurio
authors: Walter
authors: W
authors: Moretti
authors: Achille
authors: A
authors: Panzeri
authors: Wilma
authors: W
authors: Pastori
authors: Paolo
authors: P
authors: Pevarello
authors: Francesca
authors: F
authors: Quartieri
authors: Fulvia
authors: F
authors: Roletto
authors: Gabriella
authors: G
authors: Traquandi
authors: Paola
authors: P
authors: Vianello
authors: Anna
authors: A
authors: Vulpetti
authors: Marina
authors: M
authors: Ciomei
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; C550092:N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo(4,3-h)quinazoline-3-carboxamide; D011720:Pyrazoles; D011799:Quinazolines; D018844:Cyclin-Dependent Kinases