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Molibresib (I-BET-762)

別名: GSK525762, GSK525762A

Molibresib (I-BET-762, GSK525762, GSK525762A) 是一種BET蛋白抑制劑,無(wú)細(xì)胞試驗(yàn)中IC50約為35 nM,抑制巨噬細(xì)胞產(chǎn)生促炎性蛋白質(zhì),并抑制急性炎癥,對(duì)其他溴區(qū)結(jié)合域包含的蛋白具有高度選擇性。

Molibresib (I-BET-762) Chemical Structure

Molibresib (I-BET-762) Chemical Structure

CAS: 1260907-17-2

規(guī)格 價(jià)格 庫(kù)存 購(gòu)買(mǎi)數(shù)量
10mM (1mL in DMSO) 2211.3 現(xiàn)貨
2mg 958.23 現(xiàn)貨
10mg 2858.31 現(xiàn)貨
50mg 7944.3 現(xiàn)貨
100mg 13678.17 現(xiàn)貨
1g 48895.1 現(xiàn)貨
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Molibresib (I-BET-762)相關(guān)產(chǎn)品

相關(guān)信號(hào)通路圖

細(xì)胞實(shí)驗(yàn)數(shù)據(jù)示例

細(xì)胞系 實(shí)驗(yàn)類(lèi)型 給藥濃度 孵育時(shí)間 活性描述 文獻(xiàn)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
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生物活性

產(chǎn)品描述 Molibresib (I-BET-762, GSK525762, GSK525762A) 是一種BET蛋白抑制劑,無(wú)細(xì)胞試驗(yàn)中IC50約為35 nM,抑制巨噬細(xì)胞產(chǎn)生促炎性蛋白質(zhì),并抑制急性炎癥,對(duì)其他溴區(qū)結(jié)合域包含的蛋白具有高度選擇性。
靶點(diǎn)
BET proteins [1]
(Cell-free assay)
35 nM
體外研究(In Vitro)
體外研究活性 I-BET-762抑制BET(溴區(qū)和額外的末端結(jié)構(gòu)域) 蛋白, BRD2, BRD3 和 BRD4, 結(jié)合到BET的串聯(lián)溴區(qū),Kd為50.5-61.3 nM, 在FRET分析中,置換BET串聯(lián)溴區(qū)的一種四乙?;腍4肽,IC50為32.5-42.5 nM。I-BET-762占據(jù)BET蛋白的乙酰基-賴(lài)氨酸結(jié)合口袋,并抑制BET蛋白結(jié)合到乙酰化的組蛋白,從而破壞了炎性基因表達(dá)必不可少的染色質(zhì)復(fù)合物的形成。[1]分化過(guò)程中的第2天使用I-BET-762處理,改變CD4+T細(xì)胞的細(xì)胞因子產(chǎn)生,上調(diào)一些抗炎基因產(chǎn)物的表達(dá),并下調(diào)一些促炎細(xì)胞因子的表達(dá)。[2]
激酶實(shí)驗(yàn) 熒光共振能量轉(zhuǎn)移(FRET)滴定
在有四乙?;慕M蛋白H4肽(200 nM)存在時(shí),在50 mM HEPES pH7.5, 50 mM NaCl, 0.5 mM CHAPS中進(jìn)行對(duì)BRD2 (200 nM), BRD3 (100 nM) 和 BRD4 (50 nM)的I-BET滴定。平衡1小時(shí)后,在含0.05% (v/v) BSA 和 400 mM KF的實(shí)驗(yàn)緩沖液中加入2nM 銪穴狀化合物標(biāo)記的鏈霉親和素和10 nM XL-665標(biāo)記的anti-6His 抗體,使用FRET檢測(cè)溴區(qū)蛋白:肽相互作用。使用Envision酶標(biāo)儀(激發(fā)菠菜320 nm,發(fā)射波長(zhǎng)615 nm和665 nm)對(duì)實(shí)驗(yàn)板進(jìn)行讀數(shù)。
細(xì)胞實(shí)驗(yàn) 細(xì)胞系 CD4+ T 細(xì)胞
濃度 ~500 nM
孵育時(shí)間 60-72 小時(shí)
方法 從10到12周的小鼠淋巴結(jié)和脾中分離CD4+ T細(xì)胞,在指定細(xì)胞因子存在時(shí),使用與板結(jié)合的anti-CD3和anti-CD28抗體活化。在最初激活的60-72小時(shí),包含I-BET-762化合物。在T細(xì)胞培養(yǎng)和擴(kuò)張的5天過(guò)程中,化合物稀釋到初始濃度的12倍。
實(shí)驗(yàn)圖片 檢測(cè)方法 檢測(cè)指標(biāo) 實(shí)驗(yàn)圖片 PMID
Growth inhibition assay Cell viability 26840085
體內(nèi)研究(In Vivo)
體內(nèi)研究活性 I-BET-762保護(hù)防止脂多糖誘導(dǎo)的內(nèi)毒素休克和細(xì)菌誘導(dǎo)的膿毒病。LPS注射后1.5小時(shí),單劑量I-BET處理,可治愈小鼠。I-BET每日兩次注射,持續(xù)2天,保護(hù)小鼠免于膿毒癥引起的死亡。[1]早期I-BET-762處理實(shí)驗(yàn)性自身免疫性腦脊髓炎(EAE)小鼠模型,抑制Th1分化的2D2 T細(xì)胞誘發(fā)神經(jīng)性炎癥的能力。[2]
動(dòng)物實(shí)驗(yàn) Animal Models 小鼠
Dosages 30 mg/kg
Administration 靜脈注射
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

化學(xué)信息&溶解度

分子量 423.9 分子式

C22H22ClN5O2

CAS號(hào) 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
儲(chǔ)存條件(自收到貨起)

體外溶解度
批次:

DMSO : 84 mg/mL ( (198.15 mM) ;DMSO吸濕會(huì)降低化合物溶解度,請(qǐng)使用新開(kāi)封DMSO)

Ethanol : 42 mg/mL (99.07 mM)

Water : Insoluble

摩爾濃度計(jì)算器

體內(nèi)溶解度
批次:

現(xiàn)配現(xiàn)用,請(qǐng)按從左到右的順序依次添加,澄清后再加入下一溶劑

動(dòng)物體內(nèi)配方計(jì)算器

實(shí)驗(yàn)計(jì)算

摩爾濃度計(jì)算器

質(zhì)量 濃度 體積 分子量

動(dòng)物體內(nèi)配方計(jì)算器(澄清溶液)

第一步:請(qǐng)輸入基本實(shí)驗(yàn)信息(考慮到實(shí)驗(yàn)過(guò)程中的損耗,建議多配一只動(dòng)物的藥量)

mg/kg g μL

第二步:請(qǐng)輸入動(dòng)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(qǐng)聯(lián)系Selleck為您提供正確的澄清溶液配方)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計(jì)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,:如該濃度超過(guò)該批次藥物DMSO溶解度,請(qǐng)先聯(lián)系Selleck);

體內(nèi)配方配制方法: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: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(jìn)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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