Tipifarnib, having an ED50 of 4 nM, is a strong inhibitor of Trypanosoma Cruzi. With an IC50 of 0.86 nM for lamin B peptide and 7.9 nM for K-RasB peptide, respectively, tipifarnib inhibits the isolated human farnesyl transferases of these two biomolecules [2]. In cases of aggressive prostate cancer (PCa), tipifarnib reduces angiogenesis and cell proliferation while inducing apoptosis [3]. The quantity of exosomes in C4-2B and PC-3 cells was significantly reduced by tipifarnib (0.25 μM, 1 μM; 48 h) [3]. Alix, nSMase2, and Rab27a protein quantities in C4-2B cells are dramatically inhibited by tipifarnib (1 μM) [3]. When applied to C4-2B and PC-3 cells, tipifarnib (0.25 μM) strongly suppresses the activation of p-ERK, a downstream effector molecule of the Ras/Raf/ERK signaling pathway, but does not reduce total ERK [3]. A 30 minute exposure to tipifarnib (1.25-5 μM) causes endoplasmic reticulum stress in U937 cells, which in turn causes an imbalance in intracellular calcium homeostasis [4].

In mice, tipifarnib (10 mg/kg; intraperitoneal injection; single dose) inhibits the mortality caused by GalN/LPS by upregulating the liver anti-apoptotic protein Bcl-xL [5].

Animal/Disease Models: GalN/LPS challenge mouse[5]
Doses: 10 mg/kg; while chanllenge with GalN (400 mg/kg; IP) and LPS (32 g/kg)
Route of Administration: IP; 60 min before challenge
Experimental Results: Protected primary hepatocytes from GalN/tumor necrosis factor-induced cell death. Inhibited caspase 3 activation and upregulating antiapoptotic proteins.

[1]. Inhibition of farnesyltransferase: a rational approach to treat cancer? J Enzyme Inhib Med Chem. 2007 Apr;22(2):127-40.

[2]. 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.

[3]. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer. Sci Rep. 2018 May 25;8(1):8161.

Tipifarnib is a quinolone that is 1-methylquinolin-2-one which carries a 3-chlorophenyl and an amino(4-chlorophenyl)(1-methyl-imidazol-5-yl)methyl groups at the 4 and 6 positions, respectively (the R-isomer). It has a role as an antineoplastic agent, an EC 2.5.1.58 (protein farnesyltransferase) inhibitor and an apoptosis inducer. It is a quinolone, a member of monochlorobenzenes, a member of imidazoles and a primary amino compound.
Tipifarnib (R-115777) is a substance that is being studied in the treatment of acute myeloid leukemia (AML) and other types of cancer. It belongs to the family of drugs called farnesyltransferase inhibitors. It is also called Zarnestra. In June 2005, the FDA issued a Not Approvable Letter for Zarnestra.
Tipifarnib is a nonpeptidomimetic quinolinone with potential antineoplastic activity. Tipifarnib binds to and inhibits the enzyme farnesyl protein transferase, an enzyme involved in protein processing (farnesylation) for signal transduction. By inhibiting the farnesylation of proteins, this agent prevents the activation of Ras oncogenes, inhibits cell growth, induces apoptosis, and inhibits angiogenesis. (NCI04)

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Drug Indication
Investigated for use/treatment in colorectal cancer, leukemia (myeloid), pancreatic cancer, and solid tumors.
Treatment of head and neck epithelial malignant neoplasms

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Mechanism of Action
The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras protein, which is commonly abnormally active in cancer. After translation, RAS goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation. Isoprenylation involves the enzyme farnesyltransferase (FTase) transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-RAS protein. Also, a related enzyme geranylgeranyltransferase I (GGTase I) has the ability to transfer a geranylgeranyl group to K and N-RAS. Farnesyl is necessary to attach RAS to the cell membrane. Without attachment to the cell membrane, RAS is not able to transfer signals from membrane receptors (Reuter et al., 2000).

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Pharmacodynamics
R115777, a nonpeptidomimetic farnesyl transferase inhibitor, suppresses the growth of human pancreatic adenocarcinoma cell lines. This growth inhibition is associated with modulation in the phosphorylation levels of signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinases (ERK).

C27H22CL2N4O

489.4

488.117

192185-72-1

Tipifarnib (S enantiomer);192185-71-0

159324

White to light yellow solid powder

1.3±0.1 g/cm3

681.7±55.0 °C at 760 mmHg

211-213ºC (dec.)

366.1±31.5 °C

0.0±2.1 mmHg at 25°C

1.672

4.94

1

3

4

34

785

1

CN1C=NC=C1[C@@](C2=CC=C(C=C2)Cl)(C3=CC4=C(C=C3)N(C(=O)C=C4C5=CC(=CC=C5)Cl)C)N

PLHJCIYEEKOWNM-HHHXNRCGSA-N

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

6-[(R)-amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one

R115777; R 115777; R-115777; LX81; NSC702818; D03720; trade name Zarnestra

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1.43 mg/mL (2.92 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 14.3 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.

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Solubility in Formulation 2: 1.43 mg/mL (2.92 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.43 mg/mL (2.92 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 14.3 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly..

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Solubility in Formulation 4: 15% Captisol+citrate vehicle: 5 mg/mL

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Solubility in Formulation 5: 10 mg/mL (20.43 mM) in 20% HP-β-CD/10 mM citrate pH 2.0 (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)