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.
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.
Brasca
Maria Gabriella
MG
Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano (MI), Italy. gabriella.brasca@nervianoms.com
Amboldi
Nadia
N
Ballinari
Dario
D
Cameron
Alexander
A
Casale
Elena
E
Cervi
Giovanni
G
Colombo
Maristella
M
Colotta
Francesco
F
Croci
Valter
V
D'Alessio
Roberto
R
Fiorentini
Francesco
F
Isacchi
Antonella
A
Mercurio
Ciro
C
Moretti
Walter
W
Panzeri
Achille
A
Pastori
Wilma
W
Pevarello
Paolo
P
Quartieri
Francesca
F
Roletto
Fulvia
F
Traquandi
Gabriella
G
Vianello
Paola
P
Vulpetti
Anna
A
Ciomei
Marina
M
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
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