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LCL161
LCL-161, 一種second mitochondrial activator of caspase (SMAC, 線粒體促凋亡蛋白)模擬物, 能有效地結(jié)合并抑制多種IAPs(i.e. XIAP, c-IAP)。
LCL161 Chemical Structure
CAS: 1005342-46-0
產(chǎn)品質(zhì)控
批次：
純度：
99.99%
99.99
LCL161相關產(chǎn)品
| 相關靶點 | cIAP XIAP | 點擊展開 |
|---|---|---|
| 相關產(chǎn)品 | Birinapant BV-6 Xevinapant (AT406) GDC-0152 AZD5582 SM-164 SM-164 Tolinapant (ASTX660) | 點擊展開 |
| 相關化合物庫 | 自噬化合物庫 凋亡分子化合物庫 鐵死亡化合物庫 細胞焦亡化合物庫 線粒體靶向化合物庫 | 點擊展開 |
相關信號通路圖
細胞實驗數(shù)據(jù)示例
| 細胞系 | 實驗類型 | 給藥濃度 | 孵育時間 | 活性描述 | 文獻信息 |
|---|---|---|---|---|---|
| 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 | ||
| 點擊查看更多細胞系數(shù)據(jù) | |||||
生物活性
| 產(chǎn)品描述 | LCL-161, 一種second mitochondrial activator of caspase (SMAC, 線粒體促凋亡蛋白)模擬物, 能有效地結(jié)合并抑制多種IAPs(i.e. XIAP, c-IAP)。 | ||
|---|---|---|---|
| 靶點 |
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| 體外研究(In Vitro) | ||||
| 體外研究活性 | LCL161以高親和力與凋亡抑制蛋白因子(IAPs)結(jié)合，并啟動對cIAP1和cIAP2的破壞，其通過胱天蛋白酶的激活進一步誘導細胞凋亡。LCL161單獨給藥時適度抑制表達FLT3-ITD的細胞生長，IC50的范圍為~0.5 μM (Ba/F3-FLT3-ITD 細胞)到~4 μM (MOLM13-luc+ 細胞)。觀察到的LCL161抗D835Y突變體的效力相當高，測試抗Ba/F3-D835Y細胞時，IC50為~50 nM。LCL161 與PKC412結(jié)合治療MOLM13-luc+細胞比其任何一個藥劑單獨使用具有更顯著的細胞殺傷力，Calcusyn復合指數(shù)表明其具有協(xié)同作用。 PKC412和LCL161誘導MOLM13-luc+細胞的凋亡。PKC412 和 LCL161結(jié)合比其單獨使用能夠?qū)е赂叩募毎蛲雎省CL161通過與PKC412陽性結(jié)合，抑制基質(zhì)介導的表達FLT3的突變細胞的存活。LCL161抑制Ba/F3.p210細胞的生長，IC50為~100 nM。LCL161與ABL抑制劑，伊馬替尼結(jié)合，能夠協(xié)同抗BCR-ABL表達的細胞。對于在靶蛋白表達點突變的耐藥細胞，LCL161也具有抵抗活性。1000 nM的LCL161能夠大部分或完全殺死耐PKC412的Ba/F3衍生的細胞系，其在FLT3的ATP結(jié)合囊表達含有點突變的FLT3-ITD。100到1000 nM濃度的LCL161也表現(xiàn)出抗Ba/F3細胞的活性， Ba/F3細胞能夠表達各種伊馬替尼和尼羅替尼耐藥的BCR-ABL點突變。[1] 對LCL161抗23細胞系的評估，通過兒科臨床前測試計劃(PPTP)在體外進行96小時。對23種測試PPTP細胞系中的其中3種，10 μM濃度下的LCL161能夠抑制50%的生長。3種細胞系包括2種T細胞ALL細胞系(COG-LL-317和CCRF-CEM)，以及間變性大細胞淋巴瘤細胞系(Karpas-299)，CCRF-CEM和Karpas-299表現(xiàn)出較低的相對IC50值(分別為0.25和1.6 μM)。[2] LCL161對人體免疫亞群表現(xiàn)出免疫調(diào)節(jié)性能。用LCL161處理T淋巴細胞顯著增強具有激活作用的細胞因子分泌，對 CD4和CD8 T細胞生存或分化的作用很小。LCL161處理外周血單核細胞，在體外合成多肽存在下，顯著增強初始T細胞的啟動。髓樣樹突狀細胞在LCL161作用下表型成熟，表明降低了基于腫瘤抗原對抗疫苗的能力。這些作用可能通過觀察到的典型和非典型NF-κB途徑的激活介導，伴隨LCL161導致抗凋亡分子上調(diào)。[3] |
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|---|---|---|---|---|
| 細胞實驗 | 細胞系 | 人 T 細胞 ALL 細胞系 COG-LL-317 | ||
| 濃度 | ~10 μM | |||
| 孵育時間 | 96小時 | |||
| 方法 | 使用DIMSCAN進行體外測試 |
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| 實驗圖片 | 檢測方法 | 檢測指標 | 實驗圖片 | PMID |
| Western blot | cIAP1 / cIAP2 / XIAP / surivivin |
|
27737687 | |
| Growth inhibition assay | Cell viability |
|
27737687 | |
| 體內(nèi)研究(In Vivo) | ||
| 體內(nèi)研究活性 | LCL161顯著增強PKC412抑制Ba/F3-FLT3-ITD-luc+細胞體內(nèi)生長的能力。LCL161能夠與標準化療劑，阿糖胞苷和阿霉素陽性結(jié)合，抗FLT3-ITD表達細胞和D835Y表達細胞。與LCL161結(jié)合能夠?qū)崿F(xiàn)抑制白血病生長的累加作用。LCL161 (100 毫克/千克)增強高適度劑量對患有白血病小鼠的體內(nèi)作用。[1] 通過兒科臨床前測試程序(PPTP)測試CL161(口服給藥，一周兩次)在體內(nèi)(30 或 75 毫克/千克[實體瘤] 或100 毫克/千克 [ALL])的作用。LCL161誘導顯著的EFS在大約三分之一實體瘤異種移植物(osteosarcoma and glioblastoma) 中的分布差異，但不影響ALL異種移植物中的情況。沒有觀察到可評價客觀療效者。在體內(nèi)，LCL161對兒科臨床前模型研究表現(xiàn)出有限的單劑量活性。[2] |
|
|---|---|---|
| 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 |
化學信息&溶解度
| 分子量 | 500.63 | 分子式 | C26H33FN4O3S |
| CAS號 | 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 | ||
| 儲存條件(自收到貨起) | |||
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體外溶解度 |
DMSO : 100 mg/mL ( (199.74 mM) ；DMSO吸濕會降低化合物溶解度，請使用新開封DMSO) Ethanol : 100 mg/mL (199.74 mM) Water : Insoluble |
摩爾濃度計算器 |
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體內(nèi)溶解度 現(xiàn)配現(xiàn)用，請按從左到右的順序依次添加，澄清后再加入下一溶劑 |
動物體內(nèi)配方計算器 | ||||
實驗計算
動物體內(nèi)配方計算器（澄清溶液）
第一步：請輸入基本實驗信息（考慮到實驗過程中的損耗，建議多配一只動物的藥量）
mg/kg
g
μL
只
第二步：請輸入動物體內(nèi)配方組成（配方適用于不溶于水的藥物；不同批次藥物配方比例不同，請聯(lián)系Selleck為您提供正確的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
計算結(jié)果：
工作液濃度： mg/ml；
DMSO母液配制方法： mg 藥物溶于μL DMSO溶液（母液濃度mg/mL，注：如該濃度超過該批次藥物DMSO溶解度，請先聯(lián)系Selleck）；
體內(nèi)配方配制方法：取μL DMSO母液，加入μL PEG300，混勻澄清后加入μL Tween 80，混勻澄清后加入μL ddH2O，混勻澄清。
體內(nèi)配方配制方法：取μL DMSO母液，加入μL Corn oil，混勻澄清。
注意：1. 首先保證母液是澄清的；
2.一定要按照順序依次將溶劑加入，進行下一步操作之前必須保證上一步操作得到的是澄清的溶液，可采用渦旋、超聲或水浴加熱等物理方法助溶。
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