| Product comprising a transduction inhibitor of heterotrimeric g protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer -> Monitor Keywords |
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Product comprising a transduction inhibitor of heterotrimeric g protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancerProduct comprising a transduction inhibitor of heterotrimeric g protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090270341, Product comprising a transduction inhibitor of heterotrimeric g protein signals combined with another anti-cancer agent for therapeutic use in the treatment of cancer. Brief Patent Description - Full Patent Description - Patent Application Claims
The present invention relates to a product comprising at least one transduction inhibitor of heterotrimeric G protein signals, that preferably corresponds to general formula (I) defined below, combined with at least one other anti-cancer agent, preferably chosen from the group comprising taxol, taxol analogues, gemcitabine and prenyltransferase inhibitors, particularly the compounds of general formulae (II) or (III) defined below, for therapeutic use, simultaneously, separately or spread over a period of time, in the treatment of cancer. The development of new anti-cancer treatments occurs largely by the discovery of effective combinations between different therapeutic classes to accentuate the antitumorous effect of each class. The combination of the anti-Her-2/neu antibody and cisplatin or etoposide inhibits the proliferation of mammary tumor cells in a more significant manner than the simple addition of the effects of each product (cf. Pegram, M., et al., Oncogene, 18(1999): 2241-2251). The combination of this antibody with taxol or methotrexate shows an addition of the effects whilst its combination with 5-fluorouracyl shows an antagonism of the products (McGuire W. P. et al., Semin. Oncol. 1997 Feb. 24 (1 Suppl 2):S2-13-S2-16). The farnesyltransferase inhibitors act in synergy with agents which depolymerise microtubules (taxol, epothilones) (cf. Moasser et al., Proc. Natl. Acad. Sci. U.S.A. (1998), 95, 1369-1374). The combination of farnesyltransferase inhibitors with cytotoxic doxorubicin, cisplatin or 5-fluorouracyl shows only an addition of the effects. The heterotrimeric G proteins are, in fact, the structural association of three distinct sub-units called α, β and γ, but function as dissociable entities constituted by sub-units α on the one hand and β/γ dimers on the other. Different forms of sub-units of α, β and γ type are described. The G proteins participate in the transmission of signals outside the cell, thanks to its interaction with receptors with seven transmembrane domains, inside using different effectors including adenylate cyclase, phospholipase C or also the ionic channels. The adenylate cyclase enzyme generates cyclic adenosine monophosphate (cAMP) (cf. Gilman, Biosci. Rep. (1995), 15, 65-97). Thus it is known, that in order to activate adenylate cyclase, it is necessary form the G proteins to be transitionally in a heterotrimeric form, in which form the monomer constituted by an α sub-unit is associated with the dimer constituted by the β and γ sub-units. It is also known that for the G proteins to be found in their heterotrimeric form, they must be fixed by their y sub-units to the membrane. It is only in this situation that the signal outside the cell can activate the α sub-unit of a G protein, which can, after disassociation, modulate the effectors such as adenylate cyclase and modulate the production of cAMP. It is also known that the β/γ dimers can directly activate the effectors leading to the activation of kinases regulated by extracellular signals (ERKs) or MAP kinases. A direct link between the β/γ sub-units and the src or src-like kinases has been demonstrated (cf. Gutkind, J. Biol. Chem. (1998), 273, 1839-1842). The harmful effects of an abnormal cAMP level are also known and occur in particular at the level of the following biological functions or disorders: smell, taste, light perception, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection and immunological functions, diabetes and obesity. The Applicant has itself already described in PCT Patent Application WO 00/02881 the use of the compounds of general formula (I) as defined hereafter as G protein inhibitors. Certain products had been described previously in the PCT Patent Application WO 97/30053. Prenyltransferase inhibitors are already used in the field of cancer treatment (cf. Sebti et al., Pharmacol. Ther. (1997), 74, 103-114; Sepp-Lorenzino et al., Cancer Res. (1997), 55, 5302-5309). The usefulness of prenyltransferase inhibitors in this type of treatment comes from their action which prevents prenylation at the level of the Ras substrate. However, the prenylation of certain forms of Ras is not modified by the prenylation inhibitors (Lerner et al., Oncogene (1997), 15, 1283-1288). As far as the anti-cancer agents are concerned, prenyltransferase inhibitors are in particular described in the following Patent Applications: PCT Applications WO 97/21701, WO 97/16443, WO 98/00409, WO 96/21456, WO 97/24378, WO 97/17321, WO 97/18813, WO 95/00497; Patents U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,510,510 and U.S. Pat. No. 5,627,202. Moreover, the compounds of general formula (II) have been described in PCT Patent Application WO 00/39130. Taxol is in particular described in Merck Index, 11th ed., 1989, under heading number 9049 and in the references cited. Camptothecin analogues have in particular been described in the U.S. Pat. No. 4,894,456 and in the PCT Patent Applications WO 94/11376, WO 97/00876, WO 98/28304, WO 98/28305, WO 99/11646 and WO 99/33829. A product according to the invention offers the advantage of being able to use lower doses of the anti-cancer agents chosen, which has the main effect of reducing the toxicity of the treatment whilst obtaining a pharmacological effect with a minimum of additive. A subject of the invention is therefore a product comprising at least one transduction inhibitor of heterotrimeric G protein signals combined with at least one anti-cancer agent, preferably chosen from the group comprising taxol, taxol analogues, gemcitabine and prenyltransferase inhibitors, for therapeutic use simultaneously, separately or spread over a period of time, in the treatment of cancer. Preferably, the prenyltransferase inhibitor combined with the transduction inhibitor of heterotrimeric G protein signals is a farnesyltransferase inhibitor. Although taxol, taxol analogues, gemcitabine and prenyltransferase inhibitors are preferred, a number of other anti-cancer agents can be also combined, according to the invention, with a transduction inhibitor of heterotrimeric G protein signals, for example: enzyme inhibitors such as topoisomerase inhibitors such as camptothecin and camptothecin analogues (in the form of analogues comprising an E lactonic ring with six members such as for example the compounds described in PCT Patent Application WO 94/11376, in the form of analogues comprising an E lactonic ring with seven members such as for example the compounds described in PCT Patent Application WO 97/00876 or also in the form of open tetracyclic analogues such as for example the compounds described in the PCT Patent Application WO 99/33829), Cdc25 phosphatase inhibitors, MAP kinase or MAP kinase kinase inhibitors, protein kinase C inhibitors, tyrosine kinase inhibitors, telomerase inhibitors; inductors of apoptosis; alkylating agents such as cisplatin; anti-metabolic agents such as 5-fluorouracil; differentiation agents; cell spindle poisons; angiogenesis inhibitors; anti-hormones or antagonists of the steroid receptors; antioxidants; antisense agents; anti-p53 agents (gene therapy); chemo-prevention agents; anti-viral agents; immuno-therapeutic agents; antibodies such as heregulin. Preferably, the transduction inhibitor of heterotrimeric G protein signals is a compound of general formula (I)
corresponding to sub-formulae (IA) or (IB):
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