Tipifarnib (Zarnestra)Farnesyltransferase inhibitor,potent and specific CAS# 192185-72-1 |
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Quality Control & MSDS
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| Cas No. | 192185-72-1 | SDF | Download SDF |
| PubChem ID | 159324 | Appearance | Powder |
| Formula | C27H22Cl2N4O | M.Wt | 489.4 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 33.33 mg/mL (68.10 mM; Need ultrasonic) | ||
| Chemical Name | 6-[(R)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one | ||
| SMILES | CN1C=NC=C1C(C2=CC=C(C=C2)Cl)(C3=CC4=C(C=C3)N(C(=O)C=C4C5=CC(=CC=C5)Cl)C)N | ||
| Standard InChIKey | PLHJCIYEEKOWNM-HHHXNRCGSA-N | ||
| Standard InChI | InChI=1S/C27H22Cl2N4O/c1-32-16-31-15-25(32)27(30,18-6-9-20(28)10-7-18)19-8-11-24-23(13-19)22(14-26(34)33(24)2)17-4-3-5-21(29)12-17/h3-16H,30H2,1-2H3/t27-/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Tipifarnib (R115777) is a potent and specific inhibitor of farnesyltransferase (FTase) with IC50 of 0.6 nM. | |||||
| Targets | FTase | |||||
| IC50 | 0.6 nM | |||||
| Cell experiment: [1] | |
| Cell lines | Human leukemia cell line THP-1 |
| Preparation method | The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
| Reacting condition | 100 ng/ml LPS plus 2 μM tipifarnib. 6 time points (0, 10, 20, 30, 40 and 50h) |
| Applications | Tipifarnib showed significant inhibition of the cytokine/ MMP-9 production as early as 20 h for MCP-1 and IL-6 and 30 h for IL-1β and MMP-9. Tipifarnib showed no significant inhibition of IL-8 production. |
| Animal experiment : [1] | |
| Animal models | Female BALB/c mice (6–7 weeks old) |
| Dosage form | Tipifarnib was dissolved in 20% cyclodextran, and 50 mg/kg was orally administered to mice at 24, 17, and 1 h before intraperitoneal injection of 20 μg of LPS per mouse, 1 mg/kg. |
| Application | After treatment of 2h, tipifarnib significantly inhibited LPS-induced TNF-α production and inhibited 50% of MIP-1α and MCP-1 production. After 3h, tipifarnib inhibited about 50% of IL-6 production and almost complete inhibition of IL-1β production. IL12-p40 and -p70 induction by LPS was also inhibited by tipifarnib at 3 h, whereas IL-10 was not significantly changed at both time points. No effects of tipifarnib on LPS-induced KC were observed, consistent with in vitro results for IL-8. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: [1] Xue X, Lai K T A, Huang J F, et al. Anti-inflammatory activity in vitro and in vivo of the protein farnesyltransferase inhibitor tipifarnib. Journal of Pharmacology and Experimental Therapeutics, 2006, 317(1): 53-60. | |
Tipifarnib (Zarnestra) Dilution Calculator
Tipifarnib (Zarnestra) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.0433 mL | 10.2166 mL | 20.4332 mL | 40.8664 mL | 51.083 mL |
| 5 mM | 0.4087 mL | 2.0433 mL | 4.0866 mL | 8.1733 mL | 10.2166 mL |
| 10 mM | 0.2043 mL | 1.0217 mL | 2.0433 mL | 4.0866 mL | 5.1083 mL |
| 50 mM | 0.0409 mL | 0.2043 mL | 0.4087 mL | 0.8173 mL | 1.0217 mL |
| 100 mM | 0.0204 mL | 0.1022 mL | 0.2043 mL | 0.4087 mL | 0.5108 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Tipifarnib (also known as Zarnestra or R115777), an orally bioavailable quinolone analog of imidazole heterocyclics, is a potent and specific nonpeptidomimetic competitive inhibitor of farnesyltransferase (FTase), an enezyme mediating post-translational farnesylation of multiple protein substrates involved in tumor cell proliferation. It has demonstrated inhibition of growth and proliferation of a broad range of human tumor models (either wild-type or mutated RAS) via cytostatic rather than cytotoxic activity both in vitro and in vivo. It cell-type dependently induces apoptosis in some neoplastic cell lineages other than acute myeloid leukemia (AML), including multiple myeloma (MM) cell lines and MM cultures from patients.
Reference
P.K. Epling-Burnett and Thomas P. Loughran Jr. Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib. Expert Opin Investig Drugs. 2010; 19(5): 689-698
Jean-Pierre Armand, Alan K. Burnett, Johannes Drach, Jean-Luc Harousseau, Bob Lowenberg and Jesus San Miguel. The emerging role of targeted therapy for hematologic malignancies: update on bortezomib and tipifarnib. The Oncologist 2007, 12:281-290
Elzbieta Izbicka, David Campos, Gilbert Carrizales and Amita Patnaik. Biomarkers of anticancer activity of R115777 (tipifarnib, zarnestra) in human breast cancer models in vitro. Anticancer Research 2005; 25: 3215-3224
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Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours.[Pubmed:16251868]
Br J Cancer. 2005 Nov 28;93(11):1222-9.
This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1-7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m(-2) and cisplatin 75 mg m(-2). This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting.
Targeting of CD34+CD38- cells using Gemtuzumab ozogamicin (Mylotarg) in combination with tipifarnib (Zarnestra) in Acute Myeloid Leukaemia.[Pubmed:23013471]
BMC Cancer. 2012 Sep 26;12:431.
BACKGROUND: The CD34+CD38- subset of AML cells is enriched for resistance to current chemotherapeutic agents and considered to contribute to disease progression and relapse in Acute Myeloid Leukaemia (AML) patients following initial treatment. METHODS: Chemosensitivity in phenotypically defined subsets from 34 primary AML samples was measured by flow cytometry following 48 hr in vitro treatment with gemtuzumab ozogamicin (GO, Mylotarg) and the farnesyltransferase inhibitor tipifarnib/zarnestra. The DNA damage response was measured using flow cytometry, immunofluorescence and immunohistochemistry. RESULTS: Using a previously validated in vitro minimal residual disease model, we now show that the combination of GO (10 ng/ml) and tipifarnib (5 muM) targets the CD34+CD38- subset resulting in 65% median cell loss compared to 28% and 13% CD34+CD38- cell loss in GO-treated and tipifarnib-treated cells, respectively. Using phosphokinome profiling and immunofluorescence in the TF-1a cell line, we demonstrate that the drug combination is characterised by the activation of a DNA damage response (induction of gammaH2A.X and thr68 phosphorylation of chk2). Higher induction of gammaH2AX was found in CD34+CD38- than in CD34+CD38+ patient cells. In a model system, we show that dormancy impairs damage resolution, allowing accumulation of gammaH2AX foci. CONCLUSIONS: The chemosensitivity of the CD34+CD38- subset, combined with enhanced damage indicators, suggest that this subset is primed to favour programmed cell death as opposed to repairing damage. This interaction between tipifarnib and GO suggests a potential role in the treatment of AML.
Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide.[Pubmed:19109557]
Blood. 2009 May 14;113(20):4841-52.
The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.
Biomarkers of anticancer activity of R115777 (Tipifarnib, Zarnestra) in human breast cancer models in vitro.[Pubmed:16101130]
Anticancer Res. 2005 Sep-Oct;25(5):3215-23.
BACKGROUND: Farnesyltransferase inhibitor R115777 (Tipifamib, Zarnestra) is active in breast cancer, but its efficacy in drug combinations has not been extensively investigated. MATERIALS AND METHODS: The activity of R115777 and paclitaxel, alone and in combination, was studied in the human breast cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA-MB-231 (low HER2/neu), with cell viability and biomarkers for farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, MMP-2, MMP-9) as the endpoints. RESULTS: The drug combination resulted in additive cytotoxicity. R115777 +/- paclitaxel inhibited HDJ-2 farnesylation, up-regulated RhoB, transiently lowered (P)ERK/ERK and (P)Akt/Akt, reduced Raf-1 and MEK and inhibited secretion of VEGF and MMP-1. CONCLUSION: The effect of R115777 on prenylation biomarkers is consistent with its mechanism of action. The drug interfered with tumor growth, survival and angiogenesis pathways in breast cancer models with low or overexpressed HER2/neu receptor. The combination of R115777 with paclitaxel might offer clinical advantage over monotherapies.
