-
Maria Menichincheri,
Clara Albanese,
Cristina Alli,
Dario Ballinari,
Alberto Bargiotti,
Marina Caldarelli,
Antonella Ciavolella,
Alessandra Cirla, Maristella Colombo,
Francesco Colotta, [......],
Fulvia Roletto,
Alessandra Scolaro,
Marco Tatò,
Marcellino Tibolla,
Barbara Valsasina,
Mario Varasi,
Paola Vianello,
Daniele Volpi,
Corrado Santocanale,
Ermes Vanotti
[show abstract]
[hide abstract]
ABSTRACT: Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.
Journal of Medicinal Chemistry 10/2010; 53(20):7296-315. · 4.80 Impact Factor
-
Italo Beria,
Barbara Valsasina,
Maria Gabriella Brasca,
Walter Ceccarelli, Maristella Colombo,
Sabrina Cribioli,
Gabriele Fachin,
Ronald D Ferguson,
Francesco Fiorentini,
Laura M Gianellini,
Maria L Giorgini,
Jurgen K Moll,
Helena Posteri,
Daniele Pezzetta,
Fulvia Roletto,
Francesco Sola,
Dania Tesei,
Michele Caruso
[show abstract]
[hide abstract]
ABSTRACT: A series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives was optimized as Polo-like kinase 1 inhibitors. Extensive SAR afforded a highly potent and selective PLK1 compound. The compound showed good antiproliferative activity when tested in a panel of tumor cell lines with PLK1 related mechanism of action and with good in vivo antitumor efficacy in two xenograft models after i.v. administration.
Bioorganic & medicinal chemistry letters 09/2010; 20(22):6489-94. · 2.65 Impact Factor
-
Silvia Pezzola,
Giovanni Antonini,
Cristina Geroni,
Italo Beria, Maristella Colombo,
Massimo Broggini,
Sergio Marchini,
Nicola Mongelli,
Loris Leboffe,
Robert MacArthur,
Alessia Francesca Mozzi,
Giorgio Federici,
Anna Maria Caccuri
[show abstract]
[hide abstract]
ABSTRACT: Brostallicin is a novel and unique glutathione transferase-activated pro-drug with promising anticancer activity, currently in phase I and II clinical evaluation. In this work, we show that, in comparison with the parental cell line showing low GST levels, the cytotoxic activity of brostallicin is significantly enhanced in the human breast carcinoma MCF-7 cell line, transfected with either human GST-pi or GST-mu. Moreover, we describe in detail the interaction of brostallicin with GSH in the presence of GSTP1-1 and GSTM2-2, the predominant GST isoenzymes found within tumor cells. The experiments reported here indicate that brostallicin binds reversibly to both isoenzymes with K(d) values in the micromolar range (the affinity being higher for GSTM2-2). Direct evidence that both GSTP1-1 and GSTM2-2 isoenzymes catalyze the Michael addition reaction of GSH to brostallicin has been obtained both by an HPLC-MS technique and by a new fluorometric assay. We also saw the rapid formation of an intermediate reactive species, which is slowly converted into the final products. This intermediate, identified as the alpha-chloroamido derivative of the GSH-brostallicin adduct, is able to alkylate DNA in a sequence-specific manner and appears to be the active form of the drug. The kinetic behavior of the reaction between brostallicin and GSH, catalyzed by GSTP1-1, has been studied in detail, and a minimum kinetic scheme that suitably describes the experimental data is provided. Overall, these data fully support and extend the findings that brostallicin could be indicated for the treatment of tumor overexpressing the pi or mu class GST.
Biochemistry 12/2009; 49(1):226-35. · 3.42 Impact Factor
-
Maria Gabriella Brasca,
Nadia Amboldi,
Dario Ballinari,
Alexander Cameron,
Elena Casale,
Giovanni Cervi, Maristella Colombo,
Francesco Colotta,
Valter Croci,
Roberto D'Alessio, [......],
Walter Moretti,
Achille Panzeri,
Wilma Pastori,
Paolo Pevarello,
Francesca Quartieri,
Fulvia Roletto,
Gabriella Traquandi,
Paola Vianello,
Anna Vulpetti,
Marina Ciomei
[show abstract]
[hide abstract]
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.
Journal of Medicinal Chemistry 08/2009; 52(16):5152-63. · 4.80 Impact Factor
