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化学構造

CAS No. 1005342-46-0

サイズ 価格(税別) 在庫状況
10mM (1mL in DMSO) JPY 29000 国内在庫あり
JPY 26400 国内在庫あり
JPY 81100 国内在庫なし(納期7~10日)
JPY 167500 国内在庫あり

代表番号: 045-509-1970|電子メール:[email protected]
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LCL161関連製品

シグナル伝達経路

IAP阻害剤の選択性比較

Cell Data

Cell Lines Assay Type Concentration Incubation Time 活性情報 PMID
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
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
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
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
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
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
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
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
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
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 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
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
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
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
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
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 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
CCRF-CEM Antiproliferative assay Antiproliferative activity against human CCRF-CEM cells, GI50 = 0.25 μM. 28435526
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生物活性

製品説明 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. The combination of LCL161 and the ABL inhibitor, imatinib, is observed to be synergistic against BCR-ABL-expressing cells. 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 imatinib- and nilotinib-resistant BCR-ABL point mutations. [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]

細胞実験 細胞株 Human T-cell ALL cell lines COG-LL-317
濃度 ~10 μM
反応時間 96 hours
実験の流れ

In vitro testing is performed using DIMSCAN

実験結果図 Methods Biomarkers 結果図 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 Nilotinib and LCL161 in suppressing leukemia growth. LCL161 (100 mg/kg) enhances in vivo effects of high-moderate doses of nilotinib (100 mg/kg) 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]

動物実験 動物モデル CB17SC scid−/− female mice
投与量 30 mg/kg
投与経路 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

化学情報

分子量 500.63 化学式

C26H33FN4O3S

CAS No. 1005342-46-0 SDF Download LCL161 SDFをダウンロードする
Smiles CC(C(=O)NC(C1CCCCC1)C(=O)N2CCCC2C3=NC(=CS3)C(=O)C4=CC=C(C=C4)F)NC
保管

In vitro
Batch:

DMSO : 100 mg/mL ( (199.74 mM); 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 100 mg/mL

Water : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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