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]

[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 of 2nM and 98nm, respectively) and exhibits anti-cancer properties. It has a role as an antineoplastic agent, an EC 2.5.1.58 (protein farnesyltransferase) inhibitor, an EC 2.5.1.59 (protein geranylgeranyltransferase type I) inhibitor and a radiosensitizing agent. It contains a L-778,123 (free base).
Farnesyltransferase/Geranylgeranyltransferase Inhibitor L-778,123 is a benzonitrile derivative capable of inhibiting some prenyltransferases. L-778,123 is a dual inhibitor of farnesyl:protein and geranylgeranyl:protein transferases; both enzymes catalyze prenylation of oncoprotein KRAS, a prerequisite step in activation of KRAS in signal transduction pathway of apoptosis. Although this agent was developed in part as an anti-KRAS agent, L-778,123 failed in a Phase I trial to inhibit KRAS, which is associated with many types of solid tumors.

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.)