192185-72-1

192185-72-1 structure

Name: Tipifarnib (R115777)
Chemical Name: 6-[(R)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one
CAS Number: 192185-72-1
Molecular Formula: C₂₇H₂₂Cl₂N₄O
Molecular Weight: 489.396
Catalog: Biochemical Inhibitor Metabolism Transferase inhibitor
Create Date: 2018-08-23 20:03:31
Modify Date: 2024-01-07 12:33:41
Tipifarnib is a potent and specific farnesyltransferase (FTase) inhibitor with IC50 of 0.6 nM, and the anti-proliferative effects are most prominent in H-ras or N-ras mutant cells.

Name	6-[(R)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one
Synonyms	Zarnestra 6-[(R)-Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone S1453_Selleck tipifarnib Tipifarnib (Zarnestra) 6-[(r)-amino(4-chlorophenyl)(1-methyl-1h-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1h)-one 2(1H)-Quinolinone, 6-[(R)-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-

Description	Tipifarnib is a potent and specific farnesyltransferase (FTase) inhibitor with IC50 of 0.6 nM, and the anti-proliferative effects are most prominent in H-ras or N-ras mutant cells.
Related Catalog	Signaling Pathways >> Metabolic Enzyme/Protease >> Farnesyl Transferase Research Areas >> Cancer
Target	IC50: 0.6 nM (FTase)
In Vitro	Tipifarnib (5 μM) leads the percentage of apoptotic cells 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[2]. 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[3]. Combining Tipifarnib with 10 nM 4-OH-tamoxifen in the presence of E2 reduces the IC50 8-fold from 400 to 50 nM[4]. Tipifarnib induces apoptosis in U937 cells[5]. 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[6].
In Vivo	Tipifarnib has the light of the modest toxicity in patients and the potent reduction of graft-versus-host disease in mice, and it could help to reduce graft-versus-host disease significantly without having a negative impact on immune reconstitution[1]. Combined therapy with tamoxifen and Tipifarnib (50 mg/kg, p.o.) produces greater tumor growth inhibition when compared with either drug alone. E2 deprivation and Tipifarnib in combination results in greater growth inhibition than either E2 deprivation or Tipifarnib alone. The combination of tamoxifen and Tipifarnib results in significantly lower Ki-67 compared with either tamoxifen or Tipifarnib alone. Tipifarnib alone also reduces the CTI compared with control. The combination of tamoxifen and Tipifarnib or Tipifarnib 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[4].
Cell Assay	Steroid-depleted cells are seeded into 12-well plates at a density of appr 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 are treated with E2 plus inhibitors either alone or in combination. The 12-well plates are treated for 6 days with daily changes. Cell number is then determined using a Z1 Coulter counter. The 96-well plates are treated with a single dose and left for 96 h at which time cell viability is measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay as described previously. The interaction between Tipifarnib and 4-OH-tamoxifen is analyzed by the median effect plot method described by Chou and Talalay. Calculation of the combination index took into account a nonfixed drug ratio and is based on the assumption that the action of the two drugs is 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 are repeated thrice.
Animal Admin	Female ovariectomized Ncr foxhead nude mice are kept under sterile conditions with free access to food and water. MCF-7 xenografts are initiated by implantation of 2-mm diameter tumor fragments from established tumors. Tumor growth is maintained by E2 supplementation through i.d. injection of 17β-estradiol pellets (dose 1.7 mg over 60 days). Once tumors reach a diameter of appr 7 mm, mice are randomized to receive vehicle [20% w/v β-cyclodextrin (pH 2.5) for Tipifarnib, 50% PEG 300, 50% H2O + 1 drop 1N HCl per 3 mL for tamoxifen], Tipifarnib (50 mg/kg twice daily), tamoxifen (20 mg/kg), or a combination of both Tipifarnib and tamoxifen. Two further treatment arms are used to assess the effect of E2 withdrawal (removal of the E2 pellet) or E2 withdrawal combined with Tipifarnib (50 mg/kg twice daily). All drugs are given by oral gavage daily for 5 consecutive days followed by a 2-day rest period, for a total of 19 days. The experiment is done twice giving similar results; therefore, the growth data are combined for statistical analysis. There are six tumor-bearing animals in each group and all tumors are harvested on day 19. Tumor volumes are calculated using the formula a × b2 × π/6, where a and b are orthogonal tumor diameters and expressed as a percentage of the volume at the start of treatment (relative tumor volume). Overall statistical difference is calculated using the Kruskal-Wallace test and statistical differences between individual treatment arms are calculated using the Mann-Whitney test.
References	[1]. Hechinger AK, et al. Inhibition of protein geranylgeranylation and farnesylation protects against GvHD via effects on CD4 effector T cells. Haematologica. 2012 Jul 16. [2]. Bai F, et al. Tipifarnib-mediated suppression of T-bet-dependent signaling pathways. Cancer Immunol Immunother. 2012 Apr;61(4):523-33. [3]. Kotsianidis I, et al. In vitro effects of the farnesyltransferase inhibitor tipifarnib on myelodysplastic syndrome progenitors. Acta Haematol. 2008;120(1):51-6. [4]. Martin LA, et al. 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. Mol Cancer Ther. 2007 Sep;6(9):2 [5]. Krzykowska-Petitjean K, et al. Tipifarnib and tanespimycin show synergic proapoptotic activity in U937 cells. J Cancer Res Clin Oncol. 2012 Mar;138(3):537-44. [6]. End DW, et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res. 2001 Jan 1;61(1):131-7.

Density	1.3±0.1 g/cm3
Boiling Point	681.7±55.0 °C at 760 mmHg
Melting Point	211-213ºC (dec.)
Molecular Formula	C₂₇H₂₂Cl₂N₄O
Molecular Weight	489.396
Flash Point	366.1±31.5 °C
Exact Mass	488.117065
PSA	65.84000
LogP	4.94
Vapour Pressure	0.0±2.1 mmHg at 25°C
Index of Refraction	1.672
Storage condition	-20?C Freezer