LCL161
LCL-161, 一种second mitochondrial activator of caspase (SMAC, 线粒体促凋亡蛋白)模拟物, 能有效地结合并抑制多种IAPs(i.e. XIAP, c-IAP)。
LCL161 Chemical Structure
CAS: 1005342-46-0
产品质控
批次：
纯度：
99.99%
99.99
LCL161相关产品
| 相关靶点 | cIAP XIAP | 点击展开 |
|---|---|---|
| 相关产品 | Birinapant BV-6 Xevinapant (AT406) GDC-0152 AZD5582 SM-164 Tolinapant (ASTX660) | 点击展开 |
| 相关化合物库 | 自噬化合物库 凋亡分子化合物库 铁死亡化合物库 细胞焦亡化合物库 线粒体靶向化合物库 | 点击展开 |
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| 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 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | LCL-161, 一种second mitochondrial activator of caspase (SMAC, 线粒体促凋亡蛋白)模拟物, 能有效地结合并抑制多种IAPs(i.e. XIAP, c-IAP)。 | ||
|---|---|---|---|
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | LCL161以高亲和力与凋亡抑制蛋白因子(IAPs)结合，并启动对cIAP1和cIAP2的破坏，其通过胱天蛋白酶的激活进一步诱导细胞凋亡。LCL161单独给药时适度抑制表达FLT3-ITD的细胞生长，IC50的范围为~0.5 μM (Ba/F3-FLT3-ITD 细胞)到~4 μM (MOLM13-luc+ 细胞)。观察到的LCL161抗D835Y突变体的效力相当高，测试抗Ba/F3-D835Y细胞时，IC50为~50 nM。LCL161 与PKC412结合治疗MOLM13-luc+细胞比其任何一个药剂单独使用具有更显著的细胞杀伤力，Calcusyn复合指数表明其具有协同作用。 PKC412和LCL161诱导MOLM13-luc+细胞的凋亡。PKC412 和 LCL161结合比其单独使用能够导致更高的细胞凋亡率。LCL161通过与PKC412阳性结合，抑制基质介导的表达FLT3的突变细胞的存活。LCL161抑制Ba/F3.p210细胞的生长，IC50为~100 nM。LCL161与ABL抑制剂，伊马替尼结合，能够协同抗BCR-ABL表达的细胞。对于在靶蛋白表达点突变的耐药细胞，LCL161也具有抵抗活性。1000 nM的LCL161能够大部分或完全杀死耐PKC412的Ba/F3衍生的细胞系，其在FLT3的ATP结合囊表达含有点突变的FLT3-ITD。100到1000 nM浓度的LCL161也表现出抗Ba/F3细胞的活性， Ba/F3细胞能够表达各种伊马替尼和尼罗替尼耐药的BCR-ABL点突变。[1] 对LCL161抗23细胞系的评估，通过儿科临床前测试计划(PPTP)在体外进行96小时。对23种测试PPTP细胞系中的其中3种，10 μM浓度下的LCL161能够抑制50%的生长。3种细胞系包括2种T细胞ALL细胞系(COG-LL-317和CCRF-CEM)，以及间变性大细胞淋巴瘤细胞系(Karpas-299)，CCRF-CEM和Karpas-299表现出较低的相对IC50值(分别为0.25和1.6 μM)。[2] LCL161对人体免疫亚群表现出免疫调节性能。用LCL161处理T淋巴细胞显著增强具有激活作用的细胞因子分泌，对 CD4和CD8 T细胞生存或分化的作用很小。LCL161处理外周血单核细胞，在体外合成多肽存在下，显著增强初始T细胞的启动。髓样树突状细胞在LCL161作用下表型成熟，表明降低了基于肿瘤抗原对抗疫苗的能力。这些作用可能通过观察到的典型和非典型NF-κB途径的激活介导，伴随LCL161导致抗凋亡分子上调。[3] |
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| 细胞实验 | 细胞系 | 人 T 细胞 ALL 细胞系 COG-LL-317 | ||
| 浓度 | ~10 μM | |||
| 孵育时间 | 96小时 | |||
| 方法 | 使用DIMSCAN进行体外测试 |
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| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | cIAP1 / cIAP2 / XIAP / surivivin |
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27737687 | |
| Growth inhibition assay | Cell viability |
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27737687 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | LCL161显著增强PKC412抑制Ba/F3-FLT3-ITD-luc+细胞体内生长的能力。LCL161能够与标准化疗剂，阿糖胞苷和阿霉素阳性结合，抗FLT3-ITD表达细胞和D835Y表达细胞。与LCL161结合能够实现抑制白血病生长的累加作用。LCL161 (100 毫克/千克)增强高适度剂量对患有白血病小鼠的体内作用。[1] 通过儿科临床前测试程序(PPTP)测试CL161(口服给药，一周两次)在体内(30 或 75 毫克/千克[实体瘤] 或100 毫克/千克 [ALL])的作用。LCL161诱导显著的EFS在大约三分之一实体瘤异种移植物(osteosarcoma and glioblastoma) 中的分布差异，但不影响ALL异种移植物中的情况。没有观察到可评价客观疗效者。在体内，LCL161对儿科临床前模型研究表现出有限的单剂量活性。[2] |
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|---|---|---|
| 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 |
化学信息&溶解度
| 分子量 | 500.63 | 分子式 | C26H33FN4O3S |
| CAS号 | 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 | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 100 mg/mL ( (199.74 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 100 mg/mL (199.74 mM) Water : Insoluble |
摩尔浓度计算器 |
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体内溶解配方 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | |||||
实验计算
动物体内配方计算器（澄清溶液）
第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量）
mg/kg
g
μL
只
第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
计算结果：
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于μL DMSO溶液（母液浓度mg/mL，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
体内配方配制方法：取μL DMSO母液，加入μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入μL ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：1. 首先保证母液是澄清的；
2.一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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