product name Tipifarnib
Description: Tipifarnib (also known as R115777) is a potent and specific farnesyltransferase (FTase) inhibitor with IC50 of 0.6 nM, its anti-proliferative effects are most prominent in H-ras or N-ras mutant cells. Tipifarnib has been investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive.
References: Clin Cancer Res. 2012 Feb 15;18(4):1129-37; Cancer Immunol Immunother. 2012 Apr;61(4):523-33.
489.4
Formula
C27H22Cl2N4O
CAS No.
192185-72-1
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 14 mg/mL (28.6 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
15% Captisol+citrate vehicle: 5 mg/mL
Synonyms
R115777
other peoduct :
| In Vitro |
In vitro activity: Using Tipifarnib 5 μM for 72 hours, the percentage of apoptotic cells is significantly higher in drug-treated compared to DMSO-treated LGL T-cells. Using T-cells from healthy donors, Tipifarnib reduces the percentage of IFNγ-positive cells in a time-dependent manner. Tipifarnib reduces the amount of activated Ras in precipitates compared to DMSO. 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. This action is not due to apoptosis induction as both normal and MDS progenitors displays equivalent DiOC3 and annexin V expression up to 72 hours after exposure to Tipifarnib. Combining Tipifarnib with 10 nM 4-OH-tamoxifen in the presence of E2 reduces the IC50 8-fold from 400 to 50 nM. Tipifarnib induces apoptosis in U937 cells. In addition, Tipifarnib inhibits isolated human farnesyltransferase for a lamin B peptide and for the K-RasB peptide with IC50 of 0.86 nM and 7.9 nM, respectively. Kinase Assay: Cell Assay: MACS-selected CD34+ cells are seeded in Methocult 4435 complete 1% bovine serum albumin, 3 U/mL recombinant human (rh) erythropoietin, 0.1 mM 2-mercaptoethanol, 2 mM L-glutamine and the following cytokines: 50 ng/mL rh stem cell factor, 20 ng/mL rh GM-CSF, 20 ng/mL rh IL-3, 20 ng/mL rh IL-6 and 20 ng/mL h G-CSF. DMSO or Tipifarnib is added at the concentrations of 2.5, 10, 25 and 50 nM at day 1. All cultures are performed in duplicates and the numbers of colonies are scored after 14 days of incubation at 37 °C in a humidified incubator containing 5% CO2. |
|---|---|
| In Vivo | Ki-67 is lower in the tumors treated with E2 withdrawal plus R115777 compared with E2 withdrawal alone. The combination of tamoxifen and R115777 results in significantly lower Ki-67 compared with either tamoxifen or R115777 alone (mean of 5% versus 16.9% and 67.3%, respectively). In contrast, no significant difference in apoptotic scores is seen between the treatment groups. R115777 alone also reduces the CTI compared with control. The combination of tamoxifen and R115777 or R115777 coupled with E2 withdrawal is most effective at lowering the CTI (0.8 and 0.7, respectively), which may account for the decrease in tumor volume. |
| Animal model | Female ovariectomized Ncr foxhead nude mice |
| Formulation & Dosage | Dissolved in 20% w/v β-cyclodextrin (pH 2.5); 50 mg/kg; Oral gavage |
| References | Clin Cancer Res. 2012 Feb 15;18(4):1129-37; Cancer Immunol Immunother. 2012 Apr;61(4):523-33; Mol Cancer Ther. 2007 Sep;6(9):2458-67. |
