Home Apoptosis IAP inhibitor - Mitochondrial Metabolism chemical LCL161 For research use only.

LCL161

LCL-161, a small molecule second mitochondrial activator of caspase (SMAC) mimetic, potently binds to and inhibits multiple IAPs (i.e. XIAP, c-IAP).

LCL161 Chemical Structure

LCL161 Chemical Structure

CAS No. 1005342-46-0

Purity & Quality Control

LCL161 Related Products

Signaling Pathway

IAP Signaling Pathways

IAP Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
LOX Function assay 100 mg/kg 8 hrs Potentiation of conatumumab-induced cIAP1 degradation in human LOX cells xenografted in mouse at 100 mg/kg, po after 8 hrs by Western blotting analysis 24083782
LOX Function assay 8 hrs Potentiation of conatumumab-induced caspase 3/7 activation in human LOX cells xenografted in mouse after 8 hrs by fluorescence assay 24083782
MDA-MB-231 Function assay 2.5 to 10 uM 19 hrs Binding affinity to cIAP1 BIR3 domain in human MDA-MB-231 cells assessed as increase in TNFalpha level at 2.5 to 10 uM after 19 hrs by ELISA 24083782
BxPC3 Function assay 3.3 uM 5 days Potentiation of conatumumab-induced cytotoxicity against human BxPC3 cells at 3.3 uM after 5 days by MTS assay 24083782
HCT15 Function assay 3.3 uM 5 days Potentiation of conatumumab-induced cytotoxicity against human HCT15 cells at 3.3 uM after 5 days by MTS assay 24083782
SW620 Function assay 1.1 uM 5 days Potentiation of conatumumab-induced cytotoxicity against human SW620 cells at 1.1 uM after 5 days by MTS assay 24083782
SW620 Function assay 3.3 uM 5 days Potentiation of conatumumab-induced cytotoxicity against human SW620 cells at 3.3 uM after 5 days by MTS assay 24083782
LOX Function assay 3.3 uM 3 days Potentiation of conatumumab-induced cytotoxicity against human LOX cells at 3.3 uM after 3 days by MTS assay 24083782
LS180 Function assay 3.3 uM 5 days Potentiation of conatumumab-induced cytotoxicity against human LS180 cells at 3.3 uM after 5 days by MTS assay 24083782
H460 Function assay 3.3 uM 5 days Potentiation of conatumumab-induced cytotoxicity against human H460 cells at 3.3 uM after 5 days by MTS assay 24083782
LOX Function assay 100 mg/kg 8 hrs Plasma concentration in nude mouse xenografted with human LOX cells at 100 mg/kg, po measured at 8 hrs, Cp = 3.3 μM. 24093940
SW620 Function assay 5 days Induction of sensitization of human SW620 cells to conatumumab-induced apoptosis assessed as cell viability after 5 days by MTS assay, EC90 = 6.66 μM. 24093940
LOX Function assay 100 mg/kg 8 hrs Drug uptake in tumor of nude mouse xenografted with human LOX cells at 100 mg/kg, po measured at 8 hrs, Drug uptake = 18.4 μM. 24093940
SW620 Function assay 2.5 uM 5 days Induction of sensitization of human SW620 cells to conatumumab-induced apoptosis assessed as cell viability at 2.5 uM after 5 days by MTS assay 24093940
LOX Function assay 100 mg/kg 8 hrs In vivo inhibition of XIAP BIR2 domain in human LOX cells xenografted in nude mouse assessed as potentiation of conatumumab-induced caspase 3/7 activity at 100 mg/kg, po after 8 hrs by Western blot analysis 24093940
LOX Function assay 100 mg/kg 8 hrs In vivo inhibition of XIAP BIR2 domain in human LOX cells xenografted in nude mouse assessed as increase in caspase 3/7 activity at 100 mg/kg, po after 8 hrs by Western blot analysis 24093940
MDA-MB-231 Function assay 0.37 to 3.3 uM 19 hrs Inhibition of cIAP1/2 in human MDA-MB-231 cells assessed as induction of TNFalpha level at 0.37 to 3.3 uM after 19 hrs by ELISA 24093940
CHL1 Function assay 0.4 to 10 uM 28 hrs Inhibition of cIAP1 in human CHL1 cells at 0.4 to 10 uM after 28 hrs by Western blot analysis 24093940
SKMES1 Function assay 2.5 uM 5 days Potentiation of conatumumab-induced apoptosis in human SKMES1 cells at 2.5 uM after 5 days by MTS assay 24093940
Capan1 Function assay 2.5 uM 5 days Potentiation of conatumumab-induced apoptosis in human Capan1 cells at 2.5 uM after 5 days by MTS assay 24093940
AGS Function assay 2.5 uM 5 days Induction of sensitization of human AGS cells to conatumumab-induced apoptosis assessed as cell viability at 2.5 uM after 5 days by MTS assay 24093940
U118MG Function assay 2.5 uM 5 days Potentiation of conatumumab-induced apoptosis in human U118MG cells at 2.5 uM after 5 days by MTS assay 24093940
PC3 Function assay 2.5 uM 5 days Induction of sensitization of human PC3 cells to conatumumab-induced apoptosis assessed as cell viability at 2.5 uM after 5 days by MTS assay 24093940
CCRF-CEM Antiproliferative assay Antiproliferative activity against human CCRF-CEM cells, GI50 = 0.25 μM. 28435526
MDA-MB-231 Function assay 2 hrs Induction of cIAP1 degradation in human MDA-MB-231 cells after 2 hrs, EC50 = 0.0004 μM. 28492317
MDA-MB-231 Cytotoxicity assay 72 hrs Cytotoxicity against human MDA-MB-231 cells assessed as decrease in cell proliferation after 72 hrs by alamar blue assay, EC50 = 0.0078 μM. 28492317
HEK293 Function assay 2 hrs Inhibition of full length FLAG-tagged XIAP (unknown origin) interaction with full length untagged caspase-9 expressed in HEK293 cells after 2 hrs by immunoprecipitation assay, EC50 = 0.035 μM. 28492317
MDA-MB-231 Antitumor assay 30 mg/kg 24 days Antitumor activity against human MDA-MB-231 cells xenografted in Balb/c SCID mouse assessed as tumor growth inhibition at 30 mg/kg administered via oral gavage for 24 days 28492317
MDA-MB-231 Function assay 2 hrs Induction of intracellular cIAP1 degradation in human MDA-MB-231 cells after 2 hrs, IC50 = 0.0004 μM. 30091600
MDA-MB-231 Antiproliferative assay 72 hrs Antiproliferative activity against human MDA-MB-231 cells after 72 hrs by Alamar blue assay, IC50 = 0.0078 μM. 30091600
HEK293 Function assay 2 hrs Inhibition of full length FLAG-tagged XIAP (unknown origin) interaction with full length untagged caspase-9 expressed in HEK293 cells after 2 hrs by immunoprecipitation assay, IC50 = 0.035 μM. 30091600
SKOV3 Apoptosis assay 48 hrs Induction of apoptosis in human SKOV3 cells assessed caspase-3 activation after 48 hrs by IncuCyte S3 live-cell analysis, EC50 = 0.001 μM. 31095386
SKOV3 Apoptosis assay 24 hrs Induction of apoptosis in human SKOV3 cells assessed caspase-3 activation after 24 hrs by IncuCyte S3 live-cell analysis, EC50 = 0.003 μM. 31095386
BL21(DE3) Function assay 2 hrs Displacement of biotinylated AVPF from N-terminal His tagged recombinant human XIAP-BIR3 domain (253 to 347 residues) expressed in Escherichia coli BL21(DE3) cells incubated for 2 hrs by DELFIA, IC50 = 0.048 μM. 31095386
BL21(DE3) Function assay 8 hrs Displacement of biotinylated AVPF from N-terminal His tagged recombinant human XIAP-BIR3 domain (253 to 347 residues) expressed in Escherichia coli BL21(DE3) cells incubated for 8 hrs by DELFIA, IC50 = 0.053 μM. 31095386
A549 Function assay 1 uM 3 hrs Induction of cIAP2 degradation in human A549 cells assessed as reduction in cIAP2 protein level at 1 uM incubated for 3 hrs by Western blot analysis 31550155
SK-MEL-28 Function assay 1 uM 3 hrs Induction of cIAP1 degradation in human SK-MEL-28 cells assessed as reduction in cIAP1 protein level at 1 uM incubated for 3 hrs by Western blot analysis 31550155
SK-MEL-28 Function assay 1 uM 3 hrs Induction of cIAP2 degradation in human SK-MEL-28 cells assessed as reduction in cIAP2 protein level at 1 uM incubated for 3 hrs by Western blot analysis 31550155
HEK293T Function assay 10 uM 6 hrs Covalent binding affinity to HA-BIR3 domain of XIAP (unknown origin) expressed in HEK293T cells assessed as increase in band intensity at 10 uM incubated for 6 hrs by Western blot analysis 31550155
A549 Function assay 1 uM 3 hrs Induction of cIAP1 degradation in human A549 cells assessed as reduction in cIAP1 protein level at 1 uM incubated for 3 hrs by Western blot analysis 31550155
Click to View More Cell Line Experimental Data

Biological Activity

Description LCL-161, a small molecule second mitochondrial activator of caspase (SMAC) mimetic, potently binds to and inhibits multiple IAPs (i.e. XIAP, c-IAP).
Targets
cIAP [1] XIAP [1]
In vitro
In vitro

LCL161 binds to inhibitors of apoptosis proteins (IAPs) with high affinity and initiates the destruction of cIAP1 and cIAP2, which further induces apoptosis via caspase activation. LCL161 modestly inhibits the growth of FLT3-ITD-expressing cells when administered alone, with an IC50 ranging from ~0.5 μM (Ba/F3-FLT3-ITD cells) to ~4 μM (MOLM13-luc+ cells). The potency of LCL161 against the D835Y mutant is observed to be considerably higher, with an IC50 of ~50 nM when tested against Ba/F3-D835Y cells. Treatment of MOLM13-luc+ cells with a combination of LCL161 and PKC412 leads to significantly more killing of cells than either agent alone, with Calcusyn combination indices suggestive of synergy. PKC412 and LCL161 induces apoptosis of MOLM13-luc+ cells. The combination of PKC412 and LCL161 leads to a higher induction of apoptosis than either agent alone. LCL161 is able to override stromal-mediated rescue of mutant FLT3-expressing cells through positive combination with PKC412. LCL161 inhibits the growth of Ba/F3.p210 cells with an IC50 of ~100 nM.  LCL161 also has demonstrated activity against drug-resistant cells expressing point mutations in the target proteins. LCL161 at 1000 nM is able to mostly or completely kill Ba/F3-derived cell lines conferring resistance to PKC412, which express FLT3-ITD harboring point mutations in the ATP-binding pocket of FLT3. LCL161 also shows activity at concentrations ranging from 100 to 1000 nM against Ba/F3 cells expressing various. [1]

LCL161 is evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr. LCL161 achieves 50% growth inhibition against only 3 of the 23 tested PPTP cell lines under concentration of 10 μM. The three cell lines includes two T-cell ALL cell lines (COG-LL-317 and CCRF-CEM) and an anaplastic large cell lymphoma cell line (Karpas-299), with CCRF-CEM and Karpas-299 showing the lowest relative IC50 values (0.25 and 1.6 μM, respectively). [2]

LCL161shows immunomodulatory properties on human immune subsets. T lymphocytes treated with LCL161 demonstrates significantly enhanced cytokine secretion upon activation, with little effect on CD4 and CD8 T-cell survival or proliferation. LCL161 treatment of peripheral blood mononuclear cells significantly enhances priming of naïve T cells with synthetic peptides in vitro. Myeloid dendritic cells undergoes phenotypic maturation upon LCL161 and demonstrates a reduced capacity to cross-present a tumor antigen-based vaccine. These effects are potentially mediated through an observed activation of the canonical and non-canonical NF-κB pathways, following LCL161 with a resulting upregulation of anti-apoptotic molecules. [3]
Cell Research Cell lines Human T-cell ALL cell lines COG-LL-317
Concentrations ~10 μM
Incubation Time 96 hours
Method

In vitro testing is performed using DIMSCAN
Experimental Result Images Methods Biomarkers Images PMID
Western blot cIAP1 / cIAP2 / XIAP / surivivin 27737687
Growth inhibition assay Cell viability 27737687
In Vivo
In vivo

LCL161 significantly enhances the ability of PKC412 to inhibit the growth of Ba/F3-FLT3-ITD-luc+ cells in vivo. LCL161 is also shown to positively combine with the standard chemotherapeutic agents, Ara-c and doxorubicin, against FLT3-ITD-expressing cells and against D835Y-expressing cells. There is an additive effect achieved by combining both LCL161 in suppressing leukemia growth. LCL161 (100 mg/kg) enhances in vivo effects of high-moderate doses on leukemia burden in mice. [1]

CL161 is tested against the Pediatric Preclinical Testing Program (PPTP) in vivo panels (30 or 75 mg/kg [solid tumors] or 100 mg/kg [ALL]) administered orally twice in a week. LCL161 induces significant differences in EFS distribution in approximately one-third of solid tumor xenografts (osteosarcoma and glioblastoma), but not in ALL xenografts. No objective tumor responses are observed. In vivo LCL161 demonstrates limited single agent activity against the pediatric preclinical models studied. [2]
Animal Research Animal Models CB17SC scid−/− female mice
Dosages 30 mg/kg
Administration o.g.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03111992 Completed
Multiple Myeloma
Novartis Pharmaceuticals|Novartis
 December 18 2017 Phase 1
NCT01934634 Unknown status
Metastatic Pancreatic Cancer
US Oncology Research|Novartis Pharmaceuticals|Delta Clinical Research LLC
 March 2014 Phase 1
NCT01968915 Completed
Neoplasms
Novartis Pharmaceuticals|Novartis
 November 2013 Phase 1
NCT01617668 Completed
Breast Cancer
Novartis Pharmaceuticals|Novartis
 August 2012 Phase 2

Chemical Information & Solubility

Molecular Weight 500.63 Formula

C26H33FN4O3S
CAS No. 1005342-46-0 SDF Download LCL161 SDF
Smiles CC(C(=O)NC(C1CCCCC1)C(=O)N2CCCC2C3=NC(=CS3)C(=O)C4=CC=C(C=C4)F)NC
Storage (From the date of receipt)

In vitro
Batch:

DMSO : 100 mg/mL ( (199.74 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble


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In vivo
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Tech Support

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