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| Targets |
Tipifarnib inhibits Protein Farnesyltransferase (PFT) with an IC50 of 0.7 nM against human PFT. [1]
Tipifarnib also binds to and inhibits Trypanosoma cruzi sterol 14α-demethylase (14DM/CYP51), thereby killing the parasite. Its EC50 against cultured T. cruzi amastigotes is 4 nM. [1] |
|---|---|
| ln Vitro |
Tipifarnib exhibits potent activity against cultured Trypanosoma cruzi amastigotes with an EC50 of 4 nM. [1]
Tipifarnib shows weak inhibitory activity against isolated T. cruzi PFT enzyme but strong activity against the whole parasite by inhibiting its endogenous sterol production via binding to T. cruzi 14DM. [1] Tipifarnib has very little inhibitory activity against mammalian cytochrome P450 enzymes, including CYP3A4. [1] The cytotoxicity of tipifarnib and its analogs against a panel of mammalian cells was low, with EC50 values >5 µM for all compounds against five different cell lines (human fibrosarcoma HT-1080, human neural cells SF-539, human adenocarcinoma HCC-2998, human macrophage THP-1, and human lymphocyte CRL-8155). [1] |
| ln Vivo |
In a mouse model of acute Chagas disease, oral administration of tipifarnib (50 mg/kg twice daily) only delayed the development of high parasitemia by 3-4 days and did not protect the mice from death, in contrast to its more potent analog 2g. [1]
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| Enzyme Assay |
PFT Enzyme Assay: Recombinant rat PFT was expressed and purified. The assay was performed in a buffer (pH 7.5, 50 mM HEPES, 30 mM MgCl2, 20 mM KCl, 5 mM dithiothreitol, 0.01% Triton X-100) containing 1 µM biotinylated human lamin B carboxy-terminal peptide, 1 µCi [³H]farnesyl diphosphate, and 10 ng of purified rat PFT in a total volume of 50 µL. Inhibitor solutions in DMSO were added. Reactions were incubated at 37°C for 60 minutes and terminated by adding a stop solution and scintillation proximity assay (SPA) beads. After 30 minutes at room temperature, radioactivity was counted. IC50 values were determined by nonlinear regression analysis of percent enzyme inhibition versus log inhibitor concentration. [1]
CYP3A4 Inhibition Assay: Inhibition of recombinant human CYP3A4 enzyme was determined using a commercial high-throughput inhibitor screening kit, following the manufacturer's instructions. [1] |
| Cell Assay |
T. cruzi Growth Inhibition Assay: Compounds were screened against a β-galactosidase-expressing Tulahuen strain of T. cruzi in 96-well tissue culture plates as described previously. The assay quantifies parasite growth inhibition. [1]
Mammalian Cell Cytotoxicity Assay: Compounds were screened for cytotoxicity against five different mammalian cell lines: HT-1080 (human fibrosarcoma), SF-539 (human neural cells), HCC-2998 (human adenocarcinoma), THP-1 (human macrophage), and CRL-8155 (human lymphocyte). Cells were grown in the presence of compounds for 48 hours, and cell growth/viability was quantified using Alamar Blue. Compounds were tested at final concentrations ranging from 0.78 µM to 25 µM. [1] |
| Animal Protocol |
Pharmacokinetic Study in Mice:** **Tipifarnib** was suspended at 10 mg/mL in 20% (w/v) hydroxypropyl betacyclodextrin solution. BALB/c mice (7-8 week old females, ~20 g) received a single oral dose of 50 mg/kg via gavage (100 µL volume). Blood samples were collected from the tail at timed intervals. Plasma was separated and analyzed by LC-MS/MS to determine drug concentration. [1]
**Efficacy Study in Mice (Chagas Disease Model):** BALB/c mice were infected subcutaneously with 5 x 10³ *T. cruzi* trypomastigotes (Tulahuen strain). Treatment began on day 8 post-infection. For **tipifarnib**, mice were initially dosed at 100 mg/kg twice daily (days 8-13), but due to observed weight loss, the dose was reduced to 50 mg/kg twice daily for days 14-27. The drug was administered by oral gavage. Parasitemia was monitored by microscopic examination of tail blood. Mice that became moribund were euthanized. [1] Pharmacokinetic Study in Mice: Tipifarnib was suspended at 10 mg/mL in 20% (w/v) hydroxypropyl betacyclodextrin solution. BALB/c mice (7-8 week old females, ~20 g) received a single oral dose of 50 mg/kg via gavage (100 µL volume). Blood samples were collected from the tail at timed intervals. Plasma was separated and analyzed by LC-MS/MS to determine drug concentration. [1] Efficacy Study in Mice (Chagas Disease Model): BALB/c mice were infected subcutaneously with 5 x 10³ T. cruzi trypomastigotes (Tulahuen strain). Treatment began on day 8 post-infection. For tipifarnib, mice were initially dosed at 100 mg/kg twice daily (days 8-13), but due to observed weight loss, the dose was reduced to 50 mg/kg twice daily for days 14-27. The drug was administered by oral gavage. Parasitemia was monitored by microscopic examination of tail blood. Mice that became moribund were euthanized. [1] |
| ADME/Pharmacokinetics |
Tipifarnib is orally available with a long terminal half-life of approximately 16 hours in humans (from cited background). [1]
In mice, following a single oral dose of 50 mg/kg, tipifarnib showed a peak serum concentration (Cmax) of 5-7 µM and an elimination half-life (T1/2) of approximately 4 hours. [1] |
| Toxicity/Toxicokinetics |
Tipifarnib has dose-limiting toxicities in humans, particularly bone marrow suppression. [1]
In the mouse efficacy study, initial dosing of tipifarnib at 100 mg/kg twice daily caused weight loss, necessitating a dose reduction to 50 mg/kg twice daily. [1] Tipifarnib displays poor inhibition of the hepatic cytochrome P450 enzyme CYP3A4 (IC50 > 870 nM, inferred from Table I where 2g is 870 nM and tipifarnib is implied to be weak), indicating a lower potential for drug-drug interactions compared to azole antifungals. [1] |
| References | |
| Additional Infomation |
6-[(S)-amino-(4-chlorophenyl)-(3-methyl-4-imidazolyl)methyl]-4-(3-chlorophenyl)-1-methyl-2-quinolinone is a diarylheptane compound.
Tipifarnib is a protein farnesyltransferase (PFT) inhibitor that was in Phase III clinical trials for cancer at the time of this study. [1] It was discovered to have potent activity against Trypanosoma cruzi, the causative agent of Chagas disease, by an off-target mechanism involving inhibition of the parasite's sterol 14α-demethylase (14DM/CYP51), not its PFT. [1] This dual activity (inhibiting human PFT and T. cruzi 14DM) served as the starting point for rational drug design to create analogs with reduced PFT inhibition (to lessen human toxicity) and increased anti-parasitic activity. [1] Tipifarnib can be synthesized in eight steps from inexpensive starting materials. [1] It is usually administered orally twice per day in cancer trials. [1] |
| Molecular Formula |
C27H22CL2N4O
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|---|---|
| Molecular Weight |
489.4
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| Exact Mass |
488.117
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| Elemental Analysis |
C, 66.26; H, 4.53; Cl, 14.49; N, 11.45; O, 3.27
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| CAS # |
192185-71-0
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| Related CAS # |
Tipifarnib;192185-72-1
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| PubChem CID |
9935249
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| Appearance |
White to light yellow solid powder
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| LogP |
6.196
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
34
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| Complexity |
785
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C1N(C)C2=C(C=C([C@](C3=CC=C(Cl)C=C3)(N)C4=CN=CN4C)C=C2)C(C5=CC=CC(Cl)=C5)=C1
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| InChi Key |
PLHJCIYEEKOWNM-MHZLTWQESA-N
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| InChi Code |
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-/m0/s1
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| Chemical Name |
6-[(S)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one
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| Synonyms |
(S)-Tipifarnib; (S)-Zarnestra
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~25 mg/mL (~51.1 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0433 mL | 10.2166 mL | 20.4332 mL | |
| 5 mM | 0.4087 mL | 2.0433 mL | 4.0866 mL | |
| 10 mM | 0.2043 mL | 1.0217 mL | 2.0433 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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