Tipifarnib (trade name Zarnestra) is a potent and selective farnesyltransferase inhibitor with IC50 of 0.6 nM. Tipifarnib (R115777) inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. By inhibiting the farnesylation of proteins, this agent prevents the activation of Ras oncogenes, inhibits cell growth, induces apoptosis, and inhibits angiogenesis. Tipifarnib exerts selective in vitro toxicity against clonal MDS hematopoiesis at concentrations less than 10 nM the effect being more prominent in white cell progenitors. R115777 results in Ki-67 value of 67.3% in vivo.
|Cell lines||MCF-7 cells line|
|Preparation method||Cell Growth Assays.
Steroid-depleted cells were seeded into 12-well plates at a density of ∼1 × 104 cells per well or into 96-well plates at a density of 4,000 cells per well, in dextran-coated charcoal medium. After 24 h, monolayers were treated with E2 plus inhibitors either alone or in combination. The 12-well plates were treated for 6 days with daily changes. Cell number was then determined using a Z1 Coulter counter (Beckman Coulter). The 96-well plates were treated with a single dose and left for 96 h at which time cell viability was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as described previously (15). The interaction between R115777 and 4-OH-tamoxifen was analyzed by the median effect plot method described by Chou and Talalay (16). Calculation of the combination index took into account a nonfixed drug ratio and was based on the assumption that the action of the two drugs was mutually nonexclusive for the strict detection of synergism. A combination index < 1 indicates synergism, combination index = 1 indicates additivity, and a combination index > 1 indicates antagonism. Experiments were repeated thrice.
|Incubation time||96 h|
|Animal models||MCF-7 xenografts in Female ovariectomized Ncr foxhead nude mice|
|Formulation||20% w/v β-cyclodextrin (pH 2.5)|
|Dosages||50 mg/kg twice daily for 5 consecutive days followed by a 2-day rest period, for a total of 19 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 14 mg/mL|
A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older.
Harousseau JL, et al. Blood. 2009 Aug 6;114(6):1166-73. PMID: 19470696.
Phase II trial of tipifarnib as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor-risk features.
Karp JE, et al. Clin Cancer Res. 2008 May 15;14(10):3077-82. PMID: 18483374.
The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo.
Martin LA, et al. Mol Cancer Ther. 2007 Sep;6(9):2458-67. PMID: 17876043.
Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma.
Alsina M, et al. Blood. 2004 May 1;103(9):3271-7. PMID: 14726402.
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