[CAS NO. 1005342-46-0] LCL161
PRODUCTS SPECIFICATIONS [1005342-46-0]
DESCRIPTION [1005342-46-0]
Overview
| MDL | MFCD23160049 |
|---|---|
| Molecular Weight | 500.63 |
| Molecular Formula | C26H33FN4O3S |
| SMILES | C[C@H](NC)C(N[C@@H](C1CCCCC1)C(N2[C@H](C3=NC(C(C4=CC=C(F)C=C4)=O)=CS3)CCC2)=O)=O |
22 Publications Citing Use of MCE
- [1]Immunity. 2021 Aug 10;54(8):1758-1771.e7.
- [2]Adv Mater. 2022 Nov 25;e2208782.
- [3]Cell Death Differ. 2021 Dec 1.
- [4]Cell Death Differ. 2020 May;27(5):1569-1587.
- [5]Dev Cell. 2022 Jan 3;S1534-5807(21)01035-2.
- [6]Cell Death Dis. 2021 Jun 23;12(7):641.
- [7]Cell Death Dis. 2020 Feb 5;11(2):94.
- [8]J Med Chem. 2021 Oct 27.
- [9]J Med Chem. 2019 Oct 24;62(20):9188-9200.
- [10]J Med Chem. 2019 Jun 13;62(11):5616-5627.
- [11]J Med Chem. 2018 Jul 26;61(14):6350-6363.
- [12]Pharmacol Res. 2020 Jul;157:104800.
- [13]Am J Cancer Res. 2020 Sep 1;10(9):2813-2831.
- [14]PLoS One. 2021 Mar 26;16(3):e0248175.
- [15]Exp Mol Pathol. 7 January 2022, 104739.
- [16]Anticancer Agents Med Chem. 2020;20(6):687-699.
- [17]World J Clin Cases. 2021 Jul 6;9(19):5019-5027.
- [18]Pharmazie. 2019 Jun 1;74(6):363-368.
- [19]University of Portland. Department of Biology
- [20]für das Fach der Zahn-, Mund- und Kieferheilkunde an der Medizinischen Fakultät der Julius-Maximilians. 2020 Sep.
- [21]Department of Medical Biology. 2020 Sep.
- [22]bioRxiv. May 2, 2018.
Summary
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 (IC 50 =10.23 μM) and PLC5 (IC 50 =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 (K I of 0.797 µM and K inact 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] .
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
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] .
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
| NCT Number | Sponsor | Condition | Start Date | Phase |
|---|---|---|---|---|
| NCT01098838 | Novartis Pharmaceuticals|Novartis |
Advanced Solid Tumors
|
November 2008 | Phase 1 |
| NCT01934634 | US Oncology Research|Novartis Pharmaceuticals|Delta Clinical Research, LLC |
Metastatic Pancreatic Cancer
|
March 2014 | Phase 1 |
| NCT02649673 | SCRI Development Innovations, LLC|Novartis Pharmaceuticals |
Small Cell Lung Cancer|Ovarian Cancer
|
March 23, 2016 | Phase 1 |
| NCT01240655 | Novartis Pharmaceuticals|Novartis |
Solid Tumors
|
April 2011 | Phase 1 |
| NCT01617668 | Novartis Pharmaceuticals|Novartis |
Breast Cancer
|
August 2012 | Phase 2 |
| NCT03111992 | Novartis Pharmaceuticals|Novartis |
Multiple Myeloma
|
December 18, 2017 | Phase 1 |
| NCT02098161 | M.D. Anderson Cancer Center|National Cancer Institute (NCI)|Novartis Pharmaceuticals |
Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase|Primary Myelofibrosis|Secondary Myelofibrosis
|
December 18, 2014 | Phase 2 |
| NCT02890069 | Novartis Pharmaceuticals|Novartis |
Colorectal Cancer, Non-small Cell Lung Carcinoma (Adenocarcinoma), Triple Negative Breast Cancer, Renal Cell Carcinoma
|
October 14, 2016 | Phase 1 |
| NCT01968915 | Novartis Pharmaceuticals|Novartis |
Neoplasms
|
November 2013 | Phase 1 |
| NCT01955434 | Mayo Clinic|National Cancer Institute (NCI) |
Recurrent Plasma Cell Myeloma|Refractory Plasma Cell Myeloma
|
November 2013 | Phase 2 |
Appearance
Solid
Shipping
Room temperature in continental US; may vary elsewhere.
Storage
| Powder | -20°C | 3 years |
|---|---|---|
| 4°C | 2 years | |
| In solvent | -80°C | 6 months |
| -20°C | 1 month |
Solvent & Solubility
DMSO : 100 mg/mL ( 199.75 mM ; Need ultrasonic)
Stock Solutions
| Concentration Solvent Mass | 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 |
References
- [1] Maria Ahn, et al. Potent, Dual cIAP1/XIAP Antagonists Induce Apoptosis in a Melanoma Stem Cell Population.
- [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.