Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing

Maria Gabriella Brasca, Clara Albanese, Rachele Alzani, Raffaella Amici, Nilla Avanzi, Dario Ballinari, James Bischoff, Daniela Borghi, Elena Casale, Valter Croci, Francesco Fiorentini, Antonella Isacchi, Ciro Mercurio, Marcella Nesi, Paolo Orsini, Wilma Pastori, Enrico Pesenti, Paolo Pevarello, Patrick Roussel, Mario VarasiDaniele Volpi, Anna Vulpetti, Marina Ciomei

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1844-1853
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number5
DOIs
Publication statusPublished - Mar 1 2010

Keywords

  • Anti-cancer
  • CDK
  • Cell cycle
  • Cyclin dependent kinases
  • Kinase
  • Kinase inhibitor
  • Tumor cell proliferation inhibition

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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