The research for new anticancer drugs is one of the hottest frontiers of pharmaceutical chemistry. The world market for anti-cancer chemotherapeutic drugs in 2008 reached a total turnover of 3500 million. In Italy, the antineoplastic drugs account for 1.1% of health expenditure to total 320 million dedicated to targeted therapy, a therapy with intelligent drugs such as Imatinib (Gleevec ®), which is a drug of choice for acute myeloid (AML) and chronic (AMC) leukemias, two serious cancer of the bone marrow. New intelligent drugs (CDMPs), cantharidine derivatives, which does not kill the acute and chronic myeloid leukemia cells, but block the specific system responsible for the uncontrolled cell division, have been designed, synthesized and tested in our laboratories. These compounds are potent inhibitors of protein farnesylation, a process which involves the transfer of a farnesyl moiety to the C-terminal cysteine of the target proteins. The farnesyltransferase, the enzyme responsible of that reaction, activates the regulatory mechanism of cell proliferation through the farnesylation-activation of RAS and its traslocation within cellular membrane where it runs its function. The inhibition of Ras farnesylation promotes another prenylation reaction, the RhoB geranylgeranylation, which in time gives rise to a cascade of events RhoB-geranylgeranyl i-NOSynthase-RNAm  i-NOSynthase  NO.  Apoptosis leading to increase in cellular NO concentration, a radical species potent inducer of apoptosis. Saïd M. Sebti P. Protein farnesylation: Implications for normal physiology, malignant transformation, and cancer therapy, Cancer Cell, 7, 297-300 (2005); D Weinrich, Po-Chiao Lin, P Jonkheijm, U. T. Nguyen et al: Oriented Immobilization of Farnesylated Proteins Angew. Chem. Int. 12, 2010; J. V. Heymach, F. R. KhuriH. Safran et al Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer Ann. Onc.,15, 1187-1193 (2009) Brevetto per invenzione industriale depositato dagli inventori e titolari (2009): Bolognese, A.; Lavecchia, A.; Montuori, N.; Selleri, C. Inibitori di proteine di prenilazione come agenti antitumorali: processo di preparazione ed impieghi in campo medico. Ns Rif.: NA2009A0000

Anticancer Agents for Treatment of Acute and Chronic Myeloid Leukemia. Inhibitors of Protein Prenylation (Start Cup Federico II).

MANFRA, MICHELE;
2009-01-01

Abstract

The research for new anticancer drugs is one of the hottest frontiers of pharmaceutical chemistry. The world market for anti-cancer chemotherapeutic drugs in 2008 reached a total turnover of 3500 million. In Italy, the antineoplastic drugs account for 1.1% of health expenditure to total 320 million dedicated to targeted therapy, a therapy with intelligent drugs such as Imatinib (Gleevec ®), which is a drug of choice for acute myeloid (AML) and chronic (AMC) leukemias, two serious cancer of the bone marrow. New intelligent drugs (CDMPs), cantharidine derivatives, which does not kill the acute and chronic myeloid leukemia cells, but block the specific system responsible for the uncontrolled cell division, have been designed, synthesized and tested in our laboratories. These compounds are potent inhibitors of protein farnesylation, a process which involves the transfer of a farnesyl moiety to the C-terminal cysteine of the target proteins. The farnesyltransferase, the enzyme responsible of that reaction, activates the regulatory mechanism of cell proliferation through the farnesylation-activation of RAS and its traslocation within cellular membrane where it runs its function. The inhibition of Ras farnesylation promotes another prenylation reaction, the RhoB geranylgeranylation, which in time gives rise to a cascade of events RhoB-geranylgeranyl i-NOSynthase-RNAm  i-NOSynthase  NO.  Apoptosis leading to increase in cellular NO concentration, a radical species potent inducer of apoptosis. Saïd M. Sebti P. Protein farnesylation: Implications for normal physiology, malignant transformation, and cancer therapy, Cancer Cell, 7, 297-300 (2005); D Weinrich, Po-Chiao Lin, P Jonkheijm, U. T. Nguyen et al: Oriented Immobilization of Farnesylated Proteins Angew. Chem. Int. 12, 2010; J. V. Heymach, F. R. KhuriH. Safran et al Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer Ann. Onc.,15, 1187-1193 (2009) Brevetto per invenzione industriale depositato dagli inventori e titolari (2009): Bolognese, A.; Lavecchia, A.; Montuori, N.; Selleri, C. Inibitori di proteine di prenilazione come agenti antitumorali: processo di preparazione ed impieghi in campo medico. Ns Rif.: NA2009A0000
2009
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11563/29435
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