The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease.
نویسندگان
چکیده
Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.
منابع مشابه
Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.
We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and displ...
متن کاملRational modification of a candidate cancer drug for use against Chagas disease.
Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical t...
متن کاملFarnesyltransferase inhibitor tipifarnib (ZarnestraTM, R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells. Short tile for running head: tipifarnib in polycythemia vera
Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy and chemotherapeutic agents and antithrombotic drugs. Because long term exposure to cytotoxic chemotherapy may in...
متن کاملFarnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells.
Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may inc...
متن کاملTipifarnib in the treatment of acute myeloid leukemia
Farnesyltransferase inhibitors (FTIs) are a new class of biologically active anticancer drugs. The exact anti-tumorigenic mechanism is currently unknown. FTIs inhibit farnesylation of a wide range of target proteins. In preclinical models, tipifarnib (R115777, Zarnestra(R)), a non-peptidomimetic competitive FTI, showed great potency against leukemic cells. Although it has recently demonstrated ...
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عنوان ژورنال:
- Journal of medicinal chemistry
دوره 48 17 شماره
صفحات -
تاریخ انتشار 2005