L-778123 hydrochloride is a farnesyltransferase (FTase) inhibitor. [2]

L778123 showed weak cytotoxic activity with IC50 of 100 and 125 for A549 and HT-29 cell lines, respectively. The combination of doxorubicin and L778123 can decrease IC50 of doxorubicin in both cell lines significantly.[2]
FTI L-778,123 substantially inhibited myeloid leukemia cell proliferation as quantified by MTS assays with IC50 values ranging from 0.2 μM–1.8 μM for cell lines and 0.1 μM–161.8 μM in primary samples. [3]
L-778,123 induced a G2M blockade followed by apoptosis in NB-4 (FAB M3) cells. Western blotting demonstrated that blockade of RAS protein prenylation by L-778,123 was both time- and concentration-dependent. H-RAS prenylation in HL-60 cells was almost completely inhibited within 12 hours of treatment with 0.1, 0.5 or 1 μM L-778,123, and by 6 hours with 5 μM of the drug.[3]
Western blotting and FACS analysis showed that L-778,123 also inhibited phosphorylation of MEK-1/2 and MAPK-1/2, down-stream components of the RAS-to-MAPK signaling cascade. Treatment of HL-60 cells with L-778,123 (5 μM, 24 hours) led to approximately 40–50% lower levels of intracellular phosphorylated MEK-1/2. Similarly, L-778,123 treatment caused both time- and concentration-dependent reduction of activated, diphosphorylated MAPK-1/2 levels. Higher L-778,123 concentrations (0.5, 1 and 5 μM) potently decreased diphosphorylated MAPK-1/2 levels within 6 to 12 hours, while a lower drug concentration (0.1 μM) elicited similar effects after 36 to 48 hours.[3]
The effect of L-778,123 on T cell activation (CD71 or CD25 surface expression) was determined by flow cytometry. Peripheral blood mononuclear cell (PBMC) proliferation in the presence of L-778,123 and/or cyclosporine (CsA) was determined by [3H]thymidine incorporation. The ability of L-778,123 to inhibit IL-2 receptor signaling was investigated by measuring IL-2 induced proliferation in CTLL-2 cells and IL-2 prevention of apoptosis in activated human PBMC. L-778,123 inhibited lectin induced expression of CD71 and CD25 with IC50's of 6.48 +/- 1.31 microM and 84.1 +/- 50.0 microM, respectively. PBMC proliferation was inhibited by L-778,123 with an IC50 of 0.92 +/- 0.23 microM, and addition of CsA did not increase the potency. L-778,123 did not inhibit IL-2 and IFN-gamma production by T cells. L-778,123 abrogated IL-2 induced proliferation of CTLL-2 cells with an IC50 of 0.81 +/- 0.44 microM. However, L-778,123 minimally reversed the prosurvival effect of IL-2 in activated lymphocytes. IL-2 ligand and receptor production during T cell activation are relatively unaffected by L-778,123. However, the activation and proliferative effects of IL-2 on T cells are potently blocked by L-778,123. [4]

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L-778123 demonstrated cytotoxic activity against A549 (human alveolar basal epithelial adenocarcinoma) and HT-29 (human colonic adenocarcinoma) cell lines in a dose-dependent manner. The IC₅₀ values determined by MTT assay after 72 hours of treatment were 100.72 ± 2.16 µM for A549 cells and 125.78 ± 2.45 µM for HT-29 cells. [2]
The combination of L-778123 with doxorubicin resulted in a significant reduction in the IC₅₀ of doxorubicin in both cell lines (A549: from 3.13 µM to 1.72 µM; HT-29: from 2.75 µM to 1.52 µM), suggesting a synergistic cytotoxic effect. [2]

Cytotoxicity was assessed using the MTT assay. Cell suspensions (A549: 8,000-10,000 cells/well; HT-29: 15,000-20,000 cells/well) were seeded in 96-well plates and incubated for 24 hours to allow attachment. Cells were then treated with various concentrations (1-200 µM) of L-778123, doxorubicin, or their combination for 72 hours. After treatment, culture medium was replaced with fresh medium containing MTT reagent (2 mg/mL in PBS) and incubated for an additional 4 hours at 37°C. The medium was then discarded, and the formed formazan crystals were dissolved by adding dimethyl sulfoxide and Sorenson buffer (0.1 M NaCl, 0.1 M glycine, pH 10.5) followed by shaking for 15 minutes at 37°C. Absorbance was measured at 570 nm using a microplate reader. Cell viability was calculated based on the amount of formazan produced, and IC₅₀ values were determined by linear regression analysis. Each experiment was performed in triplicate and repeated twice. [2]

[1]. Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther. 2002 Jul;1(9):747-758.

[2]. Comparison of Cytotoxic Activity of L778123 as a Farnesyltranferase Inhibitor and Doxorubicin against A549 and HT-29 Cell Lines. Adv Pharm Bull. 2013;3(1):73-77.

[3]. The Farnesyltransferase Inhibitor (FTI) L-778,123 Displays Promising Anti-Leukemia Activity. Blood (2008); 112 (11): 2627.

[4]. Inhibition of lymphocyte activation and function by the prenylation inhibitor L-778,123. Invest New Drugs. 2005 Jan;23(1):21-9.

L-778,123 hydrochloride is the hydrochloride salt of L-778,123. It is a dual inhibitor of FPTase and GGPTase-I (IC50 values of 2 nM and 98 nM, respectively) and possesses anticancer properties. It can be used as an antitumor drug, an EC 2.5.1.58 (protein farnesyltransferase) inhibitor, an EC 2.5.1.59 (type I protein geraniol geraniol transferase) inhibitor, and a radiosensitizer. It contains L-778,123 (free base). The farnesyltransferase/geraniol geraniol transferase inhibitor L-778,123 is a benzonitrile derivative that inhibits certain isoprenyltransferases. L-778,123 is a dual inhibitor of farnesyl:protein and geraniol-geraniol:protein transferases; both enzymes catalyze the isoprenelation of the oncoprotein KRAS, a prerequisite step for KRAS activation in the apoptosis signaling pathway. Although part of the drug’s development was aimed at inhibiting KRAS, L-778,123 failed to inhibit KRAS in a phase I clinical trial, and KRAS is associated with a variety of solid tumors.

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L-778123 is an imidazole-containing peptide-mimicking farnesyltransferase inhibitor. It inhibits the farnesylation of Ras protein, a post-translational modification that is crucial for the membrane localization and biological activity of Ras protein. Mutated Ras protein is associated with approximately 30% of human cancers. [2]
Although L-778123 exhibits cytotoxic activity in vitro, its potency is far weaker than that of the classic chemotherapeutic drug doxorubicin. However, it can synergistically enhance the efficacy with doxorubicin, suggesting its potential application value in combination therapy for cancer. [2]
The synthesis of L-778123 started with 3-chloroaniline and 4-(aminomethyl)benzonitrile hydrochloride, and proceeded through 7 steps with an overall yield of 24%. The final structure was confirmed by infrared spectroscopy (IR), ¹H NMR, ¹³C NMR and liquid chromatography-mass spectrometry (LC-MS). [2]

C22H20N5OCL.HCL

442.34104

441.112

253863-00-2

L-778123;183499-57-2

216453

White to off-white solid powder

698.9ºC at 760 mmHg

376.5ºC

2.22E-19mmHg at 25°C

4.11

1

4

5

30

614

0

YNBSQYGTJLIPJS-UHFFFAOYSA-N

InChI=1S/C22H20ClN5O.ClH/c23-19-2-1-3-20(10-19)28-9-8-26(15-22(28)29)14-21-12-25-16-27(21)13-18-6-4-17(11-24)5-7-18;/h1-7,10,12,16H,8-9,13-15H2;1H

4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-1-yl)methyl)-1H-imidazol-1-yl)methyl)benzonitrile dihydrochloride

L778123 HCl; L-778,123; L 778,123 HCl; L-778123; L 778123; L778,123; L-778123 hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ≥ 25 mg/mL (~56.52 mM)
H2O : ~25 mg/mL (~56.52 mM)

Solubility in Formulation 1: ≥ 2.25 mg/mL (5.09 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 22.5 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: ≥ 2.25 mg/mL (5.09 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 22.5 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: ≥ 2.25 mg/mL (5.09 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 22.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (226.07 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), suspension solution; Need ultrasonic and adjust pH to 5 with 1M HCl.

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