Title of article :
Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing Original Research Article
Author/Authors :
Maria Gabriella Brasca، نويسنده , , Clara Albanese، نويسنده , , Rachele Alzani، نويسنده , , Raffaella Amici، نويسنده , , Nilla Avanzi، نويسنده , , Dario Ballinari، نويسنده , , James Bischoff، نويسنده , , Daniela Borghi، نويسنده , , Elena Casale، نويسنده , , Valter Croci، نويسنده , , Francesco Fiorentini، نويسنده , , Antonella Isacchi، نويسنده , , Ciro Mercurio، نويسنده , , Marcella Nesi، نويسنده , , Paolo Orsini، نويسنده , , Wilma Pastori، نويسنده , , Enrico Pesenti، نويسنده , , Paolo Pevarello، نويسنده , , Patrick Roussel، نويسنده , , Mario Varasi، نويسنده , , et al.، نويسنده ,
Abstract :
We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.
Keywords :
Tumor cell proliferation inhibition , Kinase inhibitor , CDK , cell cycle , Anti-cancer , kinase , Cyclin dependent kinases
