LCL161 is a IAP inhibitor which inhibits XIAP in HEK293 cell and cIAP1 in MDA-MB-231 cell with IC50s of 35 and 0.4 nM, respectively.
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LCL161 Chemical Structure
CAS No. : 1005342-46-0
This product is a controlled substance and not for sale in your territory.
Based on 29 publication(s) in Google Scholar
LCL161 purchased from MedChemExpress. Usage Cited in:
J Med Chem. 2018 Jul 26;61(14):6350-6363.
[Abstract]
IAP inhibitors induce degradation of IAP protein levels. MOLT4 cells are treated for 3 hr with 1 μM and propped for XIAP, cIAP1 or cIAP2. The β-actin blot is detected to ensure equal sample loading.
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Description
LCL161 is a IAP inhibitor which inhibits XIAP in HEK293 cell and cIAP1 in MDA-MB-231 cell with IC50s of 35 and 0.4 nM, respectively.
IC50 & Target
IC50: 35 nM (XIAP, in HEK293 cell), 0.40 nM (cIAP1, in MDA-MB-231)[1]
In Vitro
LCL161 shows anti-proliferative effects and reduces cell viability significantly in Hep3B (IC50=10.23 μM) and PLC5 (IC50=19.19 μM) cells in a dose-dependent manner. LCL161 induces apoptosis significantly in both the sensitive cell lines in a dose-dependent manner. LCL161 significantly down regulates the expression of cIAP1, starting at very low concentrations. LCL161 at low concentrations inhibits cIAP1 starting at the concentration of 0.5 nM[2]. LCL161 is a small molecule oral IAP antagonist in development for use in combination with cytotoxic agents. The effect of LCL161 on CYP3A4/5 (CYP3A) activity is investigated in vitro. Results in human liver microsomes indicated LCL161 inhibited CYP3A in a concentration- and time-dependent manner (KI of 0.797 μM and Kinact of 0.0803 min-1). LCL161 activates human PXR in a reporter gene assay and induced CYP3A4 mRNA up to ~5-fold in human hepatocytes[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
LCL161 Related Antibodies
In Vivo
Tumor-bearing mice are treated with vehicle or LCL161 p.o. at a dose of 50 mg/kg/day, or SC-2001 p.o. at a dose of 10 mg/kg/day, 5 days a week, or in combination for the duration of the study. Tumor growth is significantly inhibited by co-treatment with SC2001 and LCL161 and tumor size in the co-treatment group is only one third of that of the control group at the end of the study[2]. LCL161 is a first-in-class oral Smac mimetic shown to induce degradation of cIAP1 and cleavage of caspase 3 in mouse xenograft models[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Room temperature in continental US; may vary elsewhere.
Stockage
Powder
-20°C
3 years
4°C
2 years
In solvent
-80°C
2 years
-20°C
1 year
Solvant et solubilité
In Vitro:
DMSO : 100 mg/mL (199.75 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Preparing Stock Solutions
ConcentrationSolventMass
1 mg
5 mg
10 mg
1 mM
1.9975 mL
9.9874 mL
19.9748 mL
5 mM
0.3995 mL
1.9975 mL
3.9950 mL
10 mM
0.1997 mL
0.9987 mL
1.9975 mL
View the Complete Stock Solution Preparation Table
*Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles. Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.
For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day. The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Protocol 1
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: 2.5 mg/mL (4.99 mM); Suspended solution; Need ultrasonic
This protocol yields a suspended solution of 2.5 mg/mL. Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Protocol 2
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.5 mg/mL (4.99 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
Protocol 3
Add each solvent one by one: 10% DMSO 90% Corn Oil
Solubility: ≥ 2.5 mg/mL (4.99 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (25.0 mg/mL) to 900 μLCorn oil, and mix evenly.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
Dosage
mg/kg
Animal weight (per animal)
g
Dosing volume (per animal)
μL
Number of animals
Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
DMSO+
%
+
%
Tween-80
+
%
Saline
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO,
. All of co-solvents are available by MedChemExpress (MCE).
, Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration:
mg/mL
Method for preparing stock solution:
mg
drug dissolved in
μL
DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take
μL DMSO stock solution, add
μL .
μL , mix evenly, next add
μL Tween 80, mix evenly, then add
μL Saline.
Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution
If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
[2]. Chen KF, et al. Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem Pharmacol. 2012 Aug 1;84(3):268-77.
[Content Brief]
[3]. Dhuria S, et al. Time-dependent inhibition and induction of human cytochrome P4503A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects. J Clin Pharmacol. 2013 Jun;53(6):642-53.
[Content Brief]
[4]. Infante JR, et al. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014 Oct 1;32(28):3103-10.
[Content Brief]
Test cellulaire
[3]
Cells are plated (3×104 viable cells/well) in 96-well clear bottom white plates and the plates are incubated for ~24 hours at 37°C (5% CO2/95% air) in a humidified incubator. The cells (six replicate wells) are then treated with various concentrations (0.5, 1, 2.5, 5, 10, 25, or 50 µM) of LCL161, or vehicle control (0.1% DMSO, final concentration) for 24 hours in Puracyp dosing media. After the incubation period, the cells are washed with PBS, lysed and the luciferase substrate is added according to the vendor instructions. An aliquot of each well is transferred to the identical wells of black 96-well plates. The luminescence of each well is measured with a TopCount NXT Microplate Scintillation and Luminescence Counter. Cell viability is measured in separate plates treated identically to the PXR-reporter gene assay plates by measurement of ATP content of the cells using the CellTiter-Glo® Luminescent Cell Viability Assay kit. Cell viability is >80% for all treatments[3].
MCE n'a pas confirmé de manière indépendante l'exactitude de ces méthodes. Ils sont pour référence seulement.
Administration animale
[2][4]
Mice[2] Male NCr athymic nude mice (5-7 weeks of age) are used. Each mouse is inoculated s.c. in the dorsal flank with 1×106 Huh-7 cells suspended in 0.1 mL of serum-free medium containing 50% Matrigel. When tumors reach 200-300 mm3, mice receives LCL161 (50 mg/kg) or SC-2001 (10 mg/kg) p.o., or a combination of LCL161 and SC-2001, once daily. Controls receive vehicle. Tumors are measured weekly using calipers and their volumes calculated using the following standard formula: width2×length×0.52. LCL161 is a first-in-class oral Smac mimetic shown to induce degradation of cIAP1 and cleavage of caspase 3 in mouse xenograft models . Rats[4] LCL161 is administered orally, once weekly in 21-day cycles, at a starting dose of 10 mg (calculated by using one tenth of the dose that caused severe toxicity in 10% of rats and converted to a human-equivalent dose). In the MDA-MB-231 triple-negative breast cancer xenograft model, once-weekly and twice-daily LCL161 dosing are similarly efficacious. Once weekly is better tolerated, with reduced weight loss.
MCE n'a pas confirmé de manière indépendante l'exactitude de ces méthodes. Ils sont pour référence seulement.
[2]. Chen KF, et al. Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem Pharmacol. 2012 Aug 1;84(3):268-77.
[Content Brief]
[3]. Dhuria S, et al. Time-dependent inhibition and induction of human cytochrome P4503A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects. J Clin Pharmacol. 2013 Jun;53(6):642-53.
[Content Brief]
[4]. Infante JR, et al. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014 Oct 1;32(28):3103-10.
[Content Brief]
[2]. Chen KF, et al. Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem Pharmacol. 2012 Aug 1;84(3):268-77.
[3]. Dhuria S, et al. Time-dependent inhibition and induction of human cytochrome P4503A4/5 by an oral IAP antagonist, LCL161, in vitro and in vivo in healthy subjects. J Clin Pharmacol. 2013 Jun;53(6):642-53.
[4]. Infante JR, et al. Phase I dose-escalation study of LCL161, an oral inhibitor of apoptosis proteins inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2014 Oct 1;32(28):3103-10.
Complete Stock Solution Preparation Table
*Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles. Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.
Optional Solvent
ConcentrationSolventMass
1 mg
5 mg
10 mg
25 mg
DMSO
1 mM
1.9975 mL
9.9874 mL
19.9748 mL
49.9371 mL
5 mM
0.3995 mL
1.9975 mL
3.9950 mL
9.9874 mL
10 mM
0.1997 mL
0.9987 mL
1.9975 mL
4.9937 mL
15 mM
0.1332 mL
0.6658 mL
1.3317 mL
3.3291 mL
20 mM
0.0999 mL
0.4994 mL
0.9987 mL
2.4969 mL
25 mM
0.0799 mL
0.3995 mL
0.7990 mL
1.9975 mL
30 mM
0.0666 mL
0.3329 mL
0.6658 mL
1.6646 mL
40 mM
0.0499 mL
0.2497 mL
0.4994 mL
1.2484 mL
50 mM
0.0399 mL
0.1997 mL
0.3995 mL
0.9987 mL
60 mM
0.0333 mL
0.1665 mL
0.3329 mL
0.8323 mL
80 mM
0.0250 mL
0.1248 mL
0.2497 mL
0.6242 mL
100 mM
0.0200 mL
0.0999 mL
0.1997 mL
0.4994 mL
LCL161 Related Classifications
Help & FAQs
Do most proteins show cross-species activity?
Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.