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Start Over Author "Edoardo Marchesi" Journal haematologica
2 results on '"Edoardo Marchesi"'

1. Characterization of compound 584, an Abl kinase inhibitor with lasting effects

Author

Miriam Puttini, Sara Redaelli, Loris Moretti, Stefania Brussolo, Rosalind H Gunby, Luca Mologni, Edoardo Marchesi, Loredana Cleris, Arianna Donella-Deana, Peter Drueckes, Elisa Sala, Vittorio Lucchini, Michael Kubbutat, Franca Formelli, Alfonso Zambon, Leonardo Scapozza, and Carlo Gambacorti-Passerini

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosome-positive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584).Design and Methods To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotrans-planted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor.Results cmp-584 showed potent anti-Abl activity both on recombinant protein (IC50: 8 nM) and in cell-based assays (IC50: 0.1–10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC50: 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib.Conclusions The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former.

Published
2008
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2. Characterization of compound 584, an Abl kinase inhibitor with lasting effects

Author

Elisa Sala, Alfonso Zambon, Stefania Brussolo, Luca Mologni, Vittorio Lucchini, Edoardo Marchesi, Loredana Cleris, Loris Moretti, Sara Redaelli, Arianna Donella-Deana, Franca Formelli, Carlo Gambacorti-Passerini, Peter Drueckes, Rosalind H. Gunby, Miriam Puttini, Michael H.G. Kubbutat, Leonardo Scapozza, Puttini, M, Redaelli, S, Moretti, L, Brussolo, S, Gunby, R, Mologni, L, Marchesi, E, Cleris, L, Donella deana, A, Drueckes, P, Sala, E, Lucchini, V, Kubbutat, M, Formelli, F, Zambon, A, Scapozza, L, and GAMBACORTI PASSERINI, C

Subjects
Abl, Imatinib analog, Off-rate, Tyrosine kinase inhibitor, Anilides, Animals, Antineoplastic Agents, Benzamides, Cell Line, Tumor, Chemistry, Pharmaceutical, Drug Resistance, Neoplasm, Humans, Imatinib Mesylate, Leukemia, Mice, Neoplasm Transplantation, Piperazines, Protein Kinase Inhibitors, Protein Structure, Tertiary, Proto-Oncogene Proteins c-abl, Pyrimidines, Drug Screening Assays, Antitumor, Hematology, medicine.drug_class, Biology, Tyrosine-kinase inhibitor, hemic and lymphatic diseases, medicine, ABL, Dasatinib, Imatinib mesylate, Nilotinib, Cancer research, imatinib, Bcr/Abl, Bosutinib, Tyrosine kinase, medicine.drug, Proto-oncogene tyrosine-protein kinase Src
Abstract

Background: Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosomepositive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584). Design and Methods: To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotransplanted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor. Results: cmp-584 showed potent anti-Abl activity both on recombinant protein (IC50: 8 nM) and in cell-based assays (IC50: 0.1-10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC50: 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib. Conclusions: The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former. ©2008 Ferrata Storti Foundation.

Published
2008

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