Molibresib (I-BET-762)
别名: GSK525762, GSK525762A
Molibresib (I-BET-762, GSK525762, GSK525762A) 是一种BET蛋白抑制剂，无细胞试验中IC50约为35 nM，抑制巨噬细胞产生促炎性蛋白质，并抑制急性炎症，对其他溴区结合域包含的蛋白具有高度选择性。
Molibresib (I-BET-762) Chemical Structure
CAS: 1260907-17-2
产品质控
批次：
纯度：
99.87%
99.87
Molibresib (I-BET-762)相关产品
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 |
|---|---|---|---|---|---|
| TY82 | Function assay | 0.2 to 1 uM | 24 hrs | Inhibition of BRD4 in human TY82 cells assessed as reduction in c-Myc protein expression at 0.2 to 1 uM after 24 hrs by Western blot analysis | 29525435 |
| TY82 | Function assay | 0.2 to 1 uM | 24 hrs | Inhibition of BRD4 in human TY82 cells assessed as reduction in c-Myc mRNA expression at 0.2 to 1 uM after 24 hrs by RT-PCR analysis | 29525435 |
| TY82 or NCI-H1299 | Function assay | 0.2 to 1 uM | 24 hrs | Inhibition of BRD4 in human TY82 or NCI-H1299 cells assessed as reduction in PD-L1 protein expression at 0.2 to 1 uM after 24 hrs by Western blot analysis | 29525435 |
| TY82 or NCI-H1299 | Function assay | 0.2 to 1 uM | 24 hrs | Inhibition of BRD4 in human TY82 or NCI-H1299 cells assessed as reduction in PD-L1 mRNA expression at 0.2 to 1 uM after 24 hrs by RT-PCR analysis | 29525435 |
| HepG2 | Function assay | 18 hrs | Induction of human ApoA1 gene expression in stably transfected human HepG2 cells coexpressing luciferase reporter gene after 18 hrs by luminescence assay, EC50 = 0.7 μM. | 21568322 | |
| HepG2 | Function assay | 6 hrs | Induction of human ApoA1 protein synthesis in human HepG2 cells assessed as neosynthesised radiolabeled protein secretion after 6 hrs by SDS PAGE analysis in presence of [35S]methionine | 21568322 | |
| HepG2 | Function assay | 18 hrs | Upregulation of ApoA1 expression in human HepG2 cells assessed as concentration required to increase 70% of luciferase activity after 18 hrs by luciferase reporter gene assay, EC170 = 0.2 μM. | 22386529 | |
| HepG2 | Function assay | 18 hrs | Induction of human ApoA1 gene expression in stably transfected human HepG2 cells coexpressing luciferase reporter gene after 18 hrs by luminescence assay, EC50 = 0.7 μM. | 22924434 | |
| Raji | Function assay | 4 hrs | Inhibition of BRD4 in human Raji cells assessed as reduction of MYC expression after 4 hrs, IC50 = 0.19 μM. | 24900758 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD3 BD2 (306 to 417 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki = 0.0303 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD4 BD2 (333 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki = 0.0323 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD4 BD1 (44 to 168 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki = 0.0388 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD2 BD2 (349 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki = 0.0492 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD3 BD1 (24 to 144 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki = 0.0539 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD2 BD1 (72 to 205 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, Ki = 0.0568 μM. | 26080064 | |
| MV4-11 | Cytotoxicity assay | 4 days | Cytotoxicity against human MV4-11 cells harboring MLL1 fusion gene assessed as growth inhibition after 4 days by CellTiter-Glo luminescent assay, IC50 = 0.093 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD4 BD2 (333 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, IC50 = 0.0984 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Displacement of FAM-labeled ZBA248 from BRD4 BD1 (44 to 168 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay, IC50 = 0.156 μM. | 26080064 | |
| MOLM13 | Cytotoxicity assay | 4 days | Cytotoxicity against human MOLM13 cells harboring MLL1 fusion gene assessed as growth inhibition after 4 days by CellTiter-Glo luminescent assay, IC50 = 0.241 μM. | 26080064 | |
| Rosetta2 DE3 | Function assay | 30 mins | Inhibition of FAM-labeled ZBA248 binding to recombinant human N-terminal His6-tagged BRD4 bromodomain 2 (333 to 460 residues) expressed in Rosetta2 DE3 cells after 30 mins by Flourescence polarization assay, Ki = 0.023 μM. | 28463487 | |
| Rosetta2 DE3 | Function assay | 30 mins | Inhibition of FAM-labeled ZBA248 binding to recombinant human N-terminal His6-tagged BRD4 bromodomain 1 (44 to 168 residues) expressed in Rosetta2 DE3 cells after 30 mins by Flourescence polarization assay, Ki = 0.0464 μM. | 28463487 | |
| Rosetta2 DE3 | Function assay | 30 mins | Inhibition of FAM-labeled ZBA248 binding to recombinant human N-terminal His6-tagged BRD4 bromodomain 2 (333 to 460 residues) expressed in Rosetta2 DE3 cells after 30 mins by Flourescence polarization assay, IC50 = 0.0775 μM. | 28463487 | |
| MV4-11 | Growth inhibition assay | 4 days | Growth inhibition of human MV4-11 cells after 4 days by WST-8 assay, IC50 = 0.093 μM. | 28463487 | |
| Rosetta2 DE3 | Function assay | 30 mins | Inhibition of FAM-labeled ZBA248 binding to recombinant human N-terminal His6-tagged BRD4 bromodomain 1 (44 to 168 residues) expressed in Rosetta2 DE3 cells after 30 mins by Flourescence polarization assay, IC50 = 0.145 μM. | 28463487 | |
| MOLM13 | Growth inhibition assay | 4 days | Growth inhibition of human MOLM13 cells after 4 days by WST-8 assay, IC50 = 0.241 μM. | 28463487 | |
| TY82 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human TY82 cells after 72 hrs by CCK8 assay, IC50 = 0.2 μM. | 28586718 | |
| MM1S | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MM1S cells after 72 hrs by CCK8 assay, IC50 = 0.23 μM. | 28586718 | |
| BL21 (DE3)-codon plus-RIL | Function assay | 4 hrs | Inhibition of JQ1-FITC binding to His6-tagged BRD4-BD1 (unknown origin) expressed in Escherichia coli BL21 (DE3)-codon plus-RIL cells incubated in dark for 4 hrs by fluorescence anisotropy assay, IC50 = 0.26 μM. | 28586718 | |
| NALM16 | Cytotoxicity assay | 5 days | Cytotoxicity against human NALM16 cells assessed as reduction in cell viability after 5 days by CellTiter-Glo assay, EC50 = 0.27 μM. | 29170024 | |
| NALM6 | Cytotoxicity assay | 5 days | Cytotoxicity against human NALM6 cells assessed as reduction in cell viability after 5 days by CellTiter-Glo assay, EC50 = 0.39 μM. | 29170024 | |
| 697 | Cytotoxicity assay | 5 days | Cytotoxicity against human 697 cells assessed as reduction in cell viability after 5 days by CellTiter-Glo assay, EC50 = 1.17 μM. | 29170024 | |
| HD-MB03 | Cytotoxicity assay | 5 days | Cytotoxicity against human HD-MB03 cells assessed as reduction in cell viability after 5 days by CellTiter-Glo assay, EC50 = 3.5 μM. | 29170024 | |
| TY82 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human TY82 cells after 72 hrs by CCK8 assay, IC50 = 0.3043 μM. | 29525435 | |
| MM1S | Antiproliferative assay | 72 hrs | Antiproliferative activity against human MM1S cells after 72 hrs by CCK8 assay, IC50 = 0.3492 μM. | 29525435 | |
| C4-2B | Antiproliferative assay | 96 hrs | Antiproliferative activity against human C4-2B cells after 96 hrs by Cell-Titer glo reagent based luminescence assay | 29541371 | |
| 22Rv1 | Antiproliferative assay | 96 hrs | Antiproliferative activity against human 22Rv1 cells after 96 hrs by Cell-Titer glo reagent based luminescence assay | 29541371 | |
| LNCAP | Antiproliferative assay | 96 hrs | Antiproliferative activity against human LNCAP cells after 96 hrs by Cell-Titer glo reagent based luminescence assay | 29541371 | |
| MV411 | Cytotoxicity assay | 72 hrs | Cytotoxicity against human MV411 cells after 72 hrs by CellTiter-Glo assay, IC50 = 0.8 μM. | 30268702 | |
| PBMC | Antiinflammatory assay | Antiinflammatory activity against human PBMC cells assessed as LPS-induced IL-6 production by chemiluminescence assay, IC50 = 0.31623 μM. | 24015967 | ||
| Rosetta2 DE3 | Function assay | Binding affinity to biotinylated BRD3 BD2 (306 to 417 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 0.0407 μM. | 26080064 | ||
| Rosetta2 DE3 | Function assay | Binding affinity to biotinylated BRD2 BD2 (349 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 0.0454 μM. | 26080064 | ||
| Rosetta2 DE3 | Function assay | Binding affinity to biotinylated BRD4 BD2 (333 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 0.0476 μM. | 26080064 | ||
| Rosetta2 DE3 | Function assay | Binding affinity to biotinylated BRD3 BD1 (24 to 144 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 0.0607 μM. | 26080064 | ||
| Rosetta2 DE3 | Function assay | Binding affinity to biotinylated BRD4 BD1 (44 to 168 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 0.0994 μM. | 26080064 | ||
| Rosetta2 DE3 | Function assay | Binding affinity to biotinylated BRD2 BD1 (72 to 205 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 0.159 μM. | 26080064 | ||
| BL21(DE3) | Function assay | Binding affinity to N-terminal His6-tagged-BRD4 bromodomain 2 (unknown origin) expressed in competent Escherichia coli BL21(DE3) cells by isothermal titration calorimetry, Kd = 0.065 μM. | 26367539 | ||
| BL21(DE3) | Function assay | Binding affinity to N-terminal His6-tagged-BRD4 bromodomain 1 (unknown origin) expressed in competent Escherichia coli BL21(DE3) cells by isothermal titration calorimetry, Kd = 0.095 μM. | 26367539 | ||
| BL21(DE3) | Function assay | Binding affinity to full length N-terminal His6-tagged-BRD2 bromodomain 2 (unknown origin) expressed in competent Escherichia coli BL21(DE3) cells by isothermal titration calorimetry, Kd = 0.1 μM. | 26367539 | ||
| BL21(DE3) | Function assay | Binding affinity to full length N-terminal His6-tagged-BRD2 bromodomain 1 (unknown origin) expressed in competent Escherichia coli BL21(DE3) cells by isothermal titration calorimetry, Kd = 0.23 μM. | 26367539 | ||
| BL21(DE3)-R3-pRARE2 | Function assay | Inhibition of human His-tagged BRD4 bromodomain 2 expressed in Escherichia coli BL21(DE3)-R3-pRARE2 cells by FRET assay, IC50 = 0.036 μM. | 26731490 | ||
| BL21(DE3)-R3-pRARE2 | Function assay | Inhibition of human His-tagged BRD4 bromodomain 1 expressed in Escherichia coli BL21(DE3)-R3-pRARE2 cells by FRET assay, IC50 = 0.036 μM. | 26731490 | ||
| THP1 | Antiproliferative assay | Antiproliferative activity against human THP1 cells, IC50 = 0.29 μM. | 28939121 | ||
| TY82 | Antiproliferative assay | Antiproliferative activity against human TY82 cells, IC50 = 0.39 μM. | 28939121 | ||
| A673 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 cells | 29435139 | ||
| DAOY | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY cells | 29435139 | ||
| Saos-2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells | 29435139 | ||
| BT-37 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 cells | 29435139 | ||
| RD | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD cells | 29435139 | ||
| MG 63 (6-TG R) | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for MG 63 (6-TG R) cells | 29435139 | ||
| NB1643 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 cells | 29435139 | ||
| OHS-50 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for OHS-50 cells | 29435139 | ||
| Rh41 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells | 29435139 | ||
| SJ-GBM2 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SJ-GBM2 cells | 29435139 | ||
| SK-N-MC | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-MC cells | 29435139 | ||
| NB-EBc1 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB-EBc1 cells | 29435139 | ||
| LAN-5 | qHTS assay | qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for LAN-5 cells | 29435139 | ||
| HL60 | Cytotoxicity assay | Cytotoxicity against human HL60 cells by MTS assay, IC50 = 0.12 μM. | 29657099 | ||
| Raji | Function assay | Inhibition of BRD4-BD1 in human Raji cells assessed as downregulation of MYC gene expression by PCR method, IC50 = 0.132 μM. | 29657099 | ||
| LNCAP | Antiproliferative assay | Antiproliferative activity against human LNCAP cells, IC50 = 0.3565 μM. | 29758518 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Molibresib (I-BET-762, GSK525762, GSK525762A) 是一种BET蛋白抑制剂，无细胞试验中IC50约为35 nM，抑制巨噬细胞产生促炎性蛋白质，并抑制急性炎症，对其他溴区结合域包含的蛋白具有高度选择性。 | ||
|---|---|---|---|
| 靶点 |
|
| 体外研究(In Vitro) | ||||
| 体外研究活性 | I-BET-762抑制BET(溴区和额外的末端结构域) 蛋白, BRD2, BRD3 和 BRD4, 结合到BET的串联溴区，Kd为50.5-61.3 nM, 在FRET分析中，置换BET串联溴区的一种四乙酰化的H4肽，IC50为32.5-42.5 nM。I-BET-762占据BET蛋白的乙酰基-赖氨酸结合口袋，并抑制BET蛋白结合到乙酰化的组蛋白，从而破坏了炎性基因表达必不可少的染色质复合物的形成。[1]分化过程中的第2天使用I-BET-762处理，改变CD4+T细胞的细胞因子产生，上调一些抗炎基因产物的表达，并下调一些促炎细胞因子的表达。[2] | |||
|---|---|---|---|---|
| 激酶实验 | 荧光共振能量转移（FRET）滴定 | |||
| 在有四乙酰化的组蛋白H4肽（200 nM）存在时，在50 mM HEPES pH7.5, 50 mM NaCl, 0.5 mM CHAPS中进行对BRD2 (200 nM), BRD3 (100 nM) 和 BRD4 (50 nM)的I-BET滴定。平衡1小时后，在含0.05% (v/v) BSA 和 400 mM KF的实验缓冲液中加入2nM 铕穴状化合物标记的链霉亲和素和10 nM XL-665标记的anti-6His 抗体，使用FRET检测溴区蛋白：肽相互作用。使用Envision酶标仪（激发菠菜320 nm，发射波长615 nm和665 nm）对实验板进行读数。 | ||||
| 细胞实验 | 细胞系 | CD4+ T 细胞 | ||
| 浓度 | ~500 nM | |||
| 孵育时间 | 60-72 小时 | |||
| 方法 | 从10到12周的小鼠淋巴结和脾中分离CD4+ T细胞，在指定细胞因子存在时，使用与板结合的anti-CD3和anti-CD28抗体活化。在最初激活的60-72小时，包含I-BET-762化合物。在T细胞培养和扩张的5天过程中，化合物稀释到初始浓度的12倍。 | |||
| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Growth inhibition assay | Cell viability |
|
26840085 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | I-BET-762保护防止脂多糖诱导的内毒素休克和细菌诱导的脓毒病。LPS注射后1.5小时，单剂量I-BET处理，可治愈小鼠。I-BET每日两次注射，持续2天，保护小鼠免于脓毒症引起的死亡。[1]早期I-BET-762处理实验性自身免疫性脑脊髓炎（EAE）小鼠模型，抑制Th1分化的2D2 T细胞诱发神经性炎症的能力。[2] | |
|---|---|---|
| 动物实验 | Animal Models | 小鼠 |
| Dosages | 30 mg/kg | |
| Administration | 静脉注射 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT03266159 | Withdrawn | Solid Tumours |
GlaxoSmithKline |
November 27 2017 | Phase 2 |
| NCT02964507 | Terminated | Neoplasms |
GlaxoSmithKline |
February 2 2017 | Phase 1 |
| NCT01943851 | Completed | Neoplasms |
GlaxoSmithKline |
May 14 2014 | Phase 2 |
| NCT01587703 | Completed | Carcinoma Midline |
GlaxoSmithKline |
March 28 2012 | Phase 1 |
化学信息&溶解度
| 分子量 | 423.9 | 分子式 | C22H22ClN5O2 |
| CAS号 | 1260907-17-2 | SDF | Download Molibresib (I-BET-762) SDF |
| Smiles | CCNC(=O)CC1C2=NN=C(N2C3=C(C=C(C=C3)OC)C(=N1)C4=CC=C(C=C4)Cl)C | ||
| 储存条件(自收到货起) | |||
|
体外溶解度 |
DMSO : 84 mg/mL ( (198.15 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 42 mg/mL (99.07 mM) Water : Insoluble |
摩尔浓度计算器 |
|
体内溶解度 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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