Home Epigenetics BET remmer I-BET151 (GSK1210151A)

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I-BET151 (GSK1210151A) BET remmer

Cat.Nr.S2780

I-BET151 (GSK1210151A) is een nieuwe selectieve BET-remmer die zich richt op BRD2, BRD3 en BRD4 met respectievelijke IC50-waarden van 0,5 μM, 0,25 μM en 0,79 μM in celvrije assays.
I-BET151 (GSK1210151A) BET remmer Chemical Structure

Chemische structuur

Moleculair gewicht: 415.44

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Kwaliteitscontrole

Batch: Zuiverheid: 99.99%
99.99

Celkweek, behandeling & werkconcentratie

Cellijnen Assaytype Concentratie Incubatietijd Formulering Activiteitsbeschrijving PMID
MV4;11 cytotoxicity assay ~100 μM DMSO IC50=26 nM 21964340
RS4;11 cytotoxicity assay ~100 μM DMSO IC50=192 nM 21964340
MOLM13 cytotoxicity assay ~100 μM DMSO IC50=120 nM 21964340
NOMO1 cytotoxicity assay ~100 μM DMSO IC50=15 nM 21964340
HEL cytotoxicity assay ~100 μM DMSO IC50=1 μM 21964340
K562 cytotoxicity assay ~100 μM DMSO IC50>100 μM 21964340
MEG01 cytotoxicity assay ~100 μM DMSO IC50=25 μM 21964340
HL60 cytotoxicity assay ~100 μM DMSO IC50=890 nM 21964340
MV4;11 Apoptosis assay ~100 μM DMSO induces apoptosis 21964340
MOLM13 Apoptosis assay ~100 μM DMSO induces apoptosis 21964340
MV4;11 Function assay DMSO decreases the recruitment of BRD3/4 and impaired recruitment of CDK9 and PAF1 to the transcriptional start site 21964340
PBMC Function assay DMSO inhibits IL-6 with pIC50 of 6.7 22437115
A2 Function assay ~10 μM DMSO reactivates latent HIV-1 23255218
A72 Function assay ~10 μM DMSO reactivates latent HIV-1 23255218
BC1 Growth inhibitory assay ~1 μM DMSO IC50=220 nM 23792448
BC3 Growth inhibitory assay ~1 μM DMSO IC50=460 nM 23792448
BCBL1 Growth inhibitory assay ~1 μM DMSO IC50=330 nM 23792448
BJAB Growth inhibitory assay ~1 μM DMSO IC50=970 nM 23792448
Namalwa Growth inhibitory assay ~1 μM DMSO IC50=970 nM 23792448
Jurkat Growth inhibitory assay ~1 μM DMSO IC50=1220 nM 23792448
MM1S Growth inhibitory assay ~1 μM DMSO IC50=760 nM 23792448
U266 Growth inhibitory assay ~1 μM DMSO IC50=950 nM 23792448
UM-PEL-1 Growth inhibitory assay ~1 μM DMSO IC50=210 nM 23792448
UM-PEL-3 Growth inhibitory assay ~1 μM DMSO IC50=180 nM 23792448
BC1 Function assay 500 nM DMSO induces cell-cycle arrest 23792448
BC3 Function assay 500 nM DMSO induces cell-cycle arrest 23792448
BC1 Function assay 800 nM DMSO reduces c-Myc protein levels 23792448
BC3 Function assay 800 nM DMSO reduces c-Myc protein levels 23792448
H929 Function assay ~1 μM DMSO induces cell cycle arrest 24335499
KMS12PE Function assay ~1 μM DMSO induces cell cycle arrest 24335499
KMS12BM Function assay ~1 μM DMSO induces cell cycle arrest 24335499
KMS18 Function assay ~1 μM DMSO induces cell cycle arrest 24335499
KMS11 Function assay ~1 μM DMSO induces cell cycle arrest 24335499
RPMI8226 Function assay ~1 μM DMSO induces cell cycle arrest 24335499
H929 Apoptosis assay ~1 μM DMSO induces cell apoptosis 24335499
KMS12PE Apoptosis assay ~1 μM DMSO induces cell apoptosis 24335499
KMS12BM Apoptosis assay ~1 μM DMSO induces cell apoptosis 24335499
KMS18 Apoptosis assay ~1 μM DMSO induces cell apoptosis 24335499
KMS11 Apoptosis assay ~1 μM DMSO induces cell apoptosis 24335499
RPMI8226 Apoptosis assay ~1 μM DMSO induces cell apoptosis 24335499
U87MG Function assay ~10 μM DMSO reduces U87MG cellular ATP with IC50 of 1.05 μM 24496381
A172 Function assay ~10 μM DMSO reduces cellular ATP with IC50 of 1.28 μM 24496381
SW1783 Function assay ~10 μM DMSO reduces cellular ATP with IC50 of 2.68 μM 24496381
U87MG Function assay ~10 μM DMSO increases proportion of cells in the G1/S transition 24496381
RAW267.4 Function assay 1 μM DMSO reduces IL-6 production induced by LPS 24859008
RAW267.4 Function assay 1 μM DMSO reduces the association between BRD4 and acetylated p65 24859008
Me007 Growth inhibitory assay ~100 μM DMSO inhibits the growth 24906137
SK-Mel-28 Growth inhibitory assay ~100 μM DMSO inhibits the growth 24906137
Mel-RMU Growth inhibitory assay ~100 μM DMSO inhibits the growth 24906137
Mel-JD Growth inhibitory assay ~100 μM DMSO inhibits the growth 24906137
Mel-RM Growth inhibitory assay ~100 μM DMSO inhibits the growth 24906137
Me007 Apoptosis assay ~100 μM DMSO induces apoptosis 24906137
SK-Mel-28 Apoptosis assay ~100 μM DMSO induces apoptosis 24906137
Mel-RMU Apoptosis assay ~100 μM DMSO induces apoptosis 24906137
Mel-JD Apoptosis assay ~100 μM DMSO induces apoptosis 24906137
Mel-RM Apoptosis assay ~100 μM DMSO induces apoptosis 24906137
Me007 Function assay 10 μM DMSO induces cell cycle arrest by upregulation of p21 24906137
SK-Mel-28 Function assay 10 μM DMSO induces cell cycle arrest by upregulation of p21 24906137
Mel-RMU Function assay 10 μM DMSO induces cell cycle arrest by upregulation of p21 24906137
Mel-JD Function assay 10 μM DMSO induces cell cycle arrest by upregulation of p21 24906137
Mel-RM Function assay 10 μM DMSO induces cell cycle arrest by upregulation of p21 24906137
Me007 Function assay 10 μM DMSO upregulates proapoptotic and cell cycle arrest genes 24906137
SK-Mel-28 Function assay 10 μM DMSO upregulates proapoptotic and cell cycle arrest genes 24906137
Mel-RMU Function assay 10 μM DMSO upregulates proapoptotic and cell cycle arrest genes 24906137
Mel-JD Function assay 10 μM DMSO upregulates proapoptotic and cell cycle arrest genes 24906137
Mel-RM Function assay 10 μM DMSO upregulates proapoptotic and cell cycle arrest genes 24906137
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 = 0.09 μM. 22386529
Raji Function assay 4 hrs Inhibition of BRD4 in human Raji cells assessed as reduction of MYC expression after 4 hrs, IC50 = 0.13 μM. 24900758
MV4-11 Growth inhibition assay 72 hrs Growth inhibition of human MV4-11 cells after 72 hrs by SRB assay, IC50 = 0.119 μM. 25559428
MM1S Growth inhibition assay 72 hrs Growth inhibition of human MM1S cells after 72 hrs by SRB assay, IC50 = 0.299 μM. 25559428
HT-29 Growth inhibition assay 72 hrs Growth inhibition of human HT-29 cells after 72 hrs by SRB assay, IC50 = 0.945 μM. 25559428
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 = 0.0317 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 = 0.162 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 = 0.226 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 = 0.228 μM. 26080064
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 = 0.0317 μM. 28463487
MV4-11 Growth inhibition assay 4 days Growth inhibition of human MV4-11 cells after 4 days by WST-8 assay, IC50 = 0.162 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 = 0.226 μM. 28463487
MOLM13 Growth inhibition assay 4 days Growth inhibition of human MOLM13 cells after 4 days by WST-8 assay, IC50 = 0.228 μM. 28463487
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 = 0.0298 μM. 26080064
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 = 0.0405 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 = 0.0528 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 = 0.0548 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 = 0.0703 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 = 0.215 μM. 26080064
Rosetta2 DE3 Function assay Binding affinity to biotinylated CREBBP (1043 to 1159 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells by bio-layer interferometry method, Kd = 3.084 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 = 0.0072 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 = 0.009 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 = 0.009 μM. 26080064
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 = 0.0223 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 = 0.0496 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 = 0.0748 μM. 26080064
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 = 0.009 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, Ki = 0.0748 μM. 28463487
THP1 Antiinflammatory assay Antiinflammatory activity in human THP1 cells 22386529
HT-29 Function assay 0.3125 uM to 5 uM 24 hrs Inhibition of BRD4 in human HT-29 cells assessed as reduction in c-Myc protein expression at 0.3125 uM to 5 uM uM after 24 hrs by Western blotting method 25559428
MV4-11 Function assay Inhibition of BRD4 in human MV4-11 cells assessed as downregulation of BCL2 RNA expression by RNA-seq analysis 29259751
MV4-11 Function assay Inhibition of BRD4 in human MV4-11 cells assessed as downregulation of cMYC RNA expression by RNA-seq analysis 29259751
U-2 OS qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for U-2 OS cells 29435139
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
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
SK-N-SH qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for SK-N-SH cells 29435139
BT-12 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 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
fibroblast cells qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for control Hh wild type fibroblast cells 29435139
Rh41 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells 29435139
Rh30 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 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
Rh18 qHTS assay qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 cells 29435139
Klik om meer experimentele gegevens over de cellijn te bekijken

Chemische informatie, Opslag en Stabiliteit

Moleculair gewicht 415.44 Formule

C23H21N5O3

 Opslag (Vanaf de ontvangstdatum)
CAS-nr. 1300031-49-5 SDF downloaden Opslag van stamoplossingen

Synoniemen N/A Smiles CC1=C(C(=NO1)C)C2=C(C=C3C(=C2)N=CC4=C3N(C(=O)N4)C(C)C5=CC=CC=N5)OC

Oplosbaarheid

In vitro
Batch:

DMSO : 83 mg/mL (199.78 mM)
(Met vocht verontreinigde DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 83 mg/mL

Water : Insoluble

Molariteitscalculator

Massa Concentratie Volume Moleculair gewicht
Verdunningscalculator Moleculair gewicht calculator

In vivo
Batch:

In vivo Formuleringscalculator (Heldere oplossing)

Stap 1: Voer de onderstaande informatie in (Aanbevolen: Een extra dier voor het geval van verlies tijdens het experiment)

mg/kg g μL

Stap 2: Voer de in vivo formulering in (Dit is alleen de calculator, geen formulering. Neem eerst contact met ons op als er geen in vivo formulering is in het gedeelte Oplosbaarheid.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

Methode voor het bereiden van DMSO-mastervloeistof: mg geneesmiddel vooraf opgelost in μL DMSO ( Concentratie mastervloeistof mg/mL, Neem eerst contact met ons op als de concentratie de DMSO-oplosbaarheid van de partij geneesmiddel overschrijdt. )

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toeμL PEG300, mengen en helder maken, voeg vervolgens toeμL Tween 80, mengen en helder maken, voeg vervolgens toe μL ddH2O, mengen en helder maken.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO mastervloeistof, voeg vervolgens toe μL Maïsolie, mengen en helder maken.

Opmerking: 1. Zorg ervoor dat de vloeistof helder is voordat u het volgende oplosmiddel toevoegt.
2. Zorg ervoor dat u het/de oplosmiddel(en) in de juiste volgorde toevoegt. U moet ervoor zorgen dat de verkregen oplossing, bij de vorige toevoeging, een heldere oplossing is voordat u verdergaat met het toevoegen van het volgende oplosmiddel. Fysische methoden zoals vortexen, echografie of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Kenmerken
Optimized to retain excellent BET target potency and selectivity while enhancing the in vivo pharmacokinetics and terminal half-life to enable prolonged in vivo studies.
Targets/IC50/Ki
BRD3
(Cell-free assay)
0.25 μM
BRD2
(Cell-free assay)
0.5 μM
BRD4
(Cell-free assay)
0.79 μM
In vitro
I-BET151 (GSK1210151A) vertoont een krachtige selectiviteit over een uitgebreid scala aan diverse eiwittypes, zoals COX-2, P450, Aurora B, GSK3β, PI3K-γ, GPCR, ionkanalen en transporters. Vergelijkbaar met I-BET762 (GSK525762A), vertoont het een krachtige bindingsaffiniteit voor BRD2, BRD3 en BRD4 met KD van 0,02-0,1 μM, en remt het significant de door lipopolysaccharide gestimuleerde IL-6-cytokineproductie in menselijke perifere bloedmononucleaire cellen (PBMC) en volbloed (WB) evenals ratten-WB met IC50 van respectievelijk 0,16 μM, 1,26 μM en 1,26 μM. Deze verbinding (0,5 of 5 μM) remt de binding van BETs (BRD2, BRD3, BRD4 en BRD9), maar niet de binding van 23 andere bromodomeine-eiwitten in HL60 nucleair extract aan geacetyleerde histonpeptiden. Het heeft een krachtige werkzaamheid tegen cellijnen die verschillende MLL-fusies bevatten, zoals MV4;11, RS4;11, MOLM13 en NOMO1-cellen met IC50 van 15-192 nM. Consistent daarmee elimineert het volledig het kolonie-vormende potentieel van MLL-fusie-gestuurde leukemieën (MOLM13), maar niet leukemieën gestuurd door tyrosinekinase-activering (K562). I-BET151 vertoont ook een krachtige werkzaamheid in zowel vloeibare kweek- als clonogene assays met primaire muizenvoorlopercellen getransformeerd met MLL-ENL of MLL-AF9. Behandeling met deze verbinding induceert significant apoptose en prominente G0/G1-arrestatie in MLL-fusie-cellijnen aangedreven door verschillende MLL-fusies (MOLM13 en MV4;11 die respectievelijk MLL-AF9 en MLL-AF4 bevatten), maar niet de K562-cellen, waarschijnlijk vanwege de remming van de transcriptie van BCL2, C-MYC en CDK6 door het blokkeren van de rekrutering van BRD3/4, PAFc en SEC-componenten naar de transcriptionele startplaats (TSS).
Kinase Assay
Fluorescentie-anisotropie (FP) ligandverplaatsingsassay
Alle componenten worden opgelost in buffer van samenstelling 50 mM HEPES pH 7.4, 150 mM NaCl en 0.5 mM CHAPS met eindconcentraties van BRD 2/3/4 75 nM, fluorescerend ligand 5 nM. 10 μL van dit reactiemengsel wordt met een micro multidrop toegevoegd aan putjes die 100 nL van verschillende concentraties I-BET151 (GSK1210151A) of DMSO-vehiculum (1% finaal) bevatten in een Greiner 384-wells zwarte microtiterplaat met laag volume en geëquilibreerd in het donker gedurende 60 minuten bij kamertemperatuur. Fluorescentie-anisotropie wordt afgelezen in Envision (lex = 485 nm, lEM = 530 nm; Dichroïsch = 505 nM).
In vivo
I-BET151 (GSK1210151A), toegediend met 30 mg/kg/dag, remt significant de tumorgroei van muizen MLL-AF9 en menselijke MLL-AF4 leukemie bij muizen, en biedt een aanzienlijk overlevingsvoordeel.
Referenties

Toepassingen

Methoden Biomarkers Afbeeldingen PMID
Western blot α-SMA / Fibronectin / Collagen-1 FoxM1 / AURKB / Survivin / cyclin B / PLK1 HP1α / HP1β / HP1γ
S2780-WB1
27732564

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