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I-BET151 (GSK1210151A) BET Bromodomain Inhibitor

Réf. Catalogue: S2780

I-BET151 (GSK1210151A) is a novel selective BET inhibitor for BRD2, BRD3 and BRD4 with IC50 of 0.5 μM, 0.25 μM, and 0.79 μM in cell-free assays, respectively.
I-BET151 (GSK1210151A) BET inhibitor Chemical Structure

Structure chimique

Poids moléculaire: 415.44

Aller à

Contrôle Qualité (Quality Control)

Lot : Pureté : 99.99%
99.99

Culture cellulaire, traitement et concentration de travail
(Cell Culture, Treatment & Working Concentration)

Lignées cellulaires Type d'essai Concentration Temps d'incubation Formulation Description de l'activité 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
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Informations chimiques, stockage et stabilité (Chemical Information, Storage & Stability)

Poids moléculaire 415.44 Formule

C23H21N5O3

 Stockage (À compter de la date de réception)
N° CAS 1300031-49-5 Télécharger le SDF Stockage des solutions mères

Synonymes 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

Solubilité (Solubility)

In vitro
Lot:

DMSO : 83 mg/mL (199.78 mM)
(Le DMSO contaminé par l'humidité peut réduire la solubilité. Utiliser du DMSO frais et anhydre.)

Ethanol : 83 mg/mL

Water : Insoluble

Calculateur de molarité

Masse Concentration Volume Poids moléculaire
Calculateur de dilution Calculateur de poids moléculaire

In vivo
Lot:

Calculateur de formulation in vivo (Solution claire)

Étape 1 : Saisir les informations ci-dessous (Recommandé : Un animal supplémentaire pour tenir compte des pertes pendant l'expérience)

mg/kg g μL

Étape 2 : Saisir la formulation in vivo (Ceci est seulement le calculateur, pas la formulation. Veuillez nous contacter d'abord s'il n'y a pas de formulation in vivo dans la section Solubilité.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Résultats du calcul :

Concentration de travail : mg/ml;

Méthode de préparation du liquide maître DMSO : mg médicament prédissous dans μL DMSO ( Concentration du liquide maître mg/mL, Veuillez nous contacter d'abord si la concentration dépasse la solubilité du DMSO du lot de médicament. )

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouterμL PEG300, mélanger et clarifier, puis ajouterμL Tween 80, mélanger et clarifier, puis ajouter μL ddH2O, mélanger et clarifier.

Méthode de préparation de la formulation in vivo : Prendre μL DMSO liquide maître, puis ajouter μL Huile de maïs, mélanger et clarifier.

Note : 1. Veuillez vous assurer que le liquide est clair avant d'ajouter le solvant suivant.
2. Assurez-vous d'ajouter le(s) solvant(s) dans l'ordre. Vous devez vous assurer que la solution obtenue, lors de l'ajout précédent, est une solution claire avant de procéder à l'ajout du solvant suivant. Des méthodes physiques telles que le vortex, les ultrasons ou le bain-marie chaud peuvent être utilisées pour faciliter la dissolution.

Mécanisme d'action (Mechanism of Action)

Caractéristiques
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) présente une sélectivité puissante sur une vaste gamme de types de protéines diverses telles que COX-2, P450, Aurora B, GSK3β, PI3K-γ, GPCR, les canaux ioniques et les transporteurs. Similaire à I-BET762 (GSK525762A), il affiche une forte affinité de liaison à BRD2, BRD3 et BRD4 avec un KD de 0,02-0,1 μM, et inhibe significativement la production de cytokines IL-6 stimulée par le lipopolysaccharide dans les cellules mononucléaires du sang périphérique humain (PBMC) et le sang total (WB) ainsi que le WB de rat avec une IC50 de 0,16 μM, 1,26 μM et 1,26 μM, respectivement. Ce composé (0,5 ou 5 μM) inhibe la liaison des BET (BRD2, BRD3, BRD4 et BRD9) mais pas la liaison de 23 autres protéines à bromodomaine dans l'extrait nucléaire HL60 aux peptides histones acétylés. Il a une efficacité puissante contre les lignées cellulaires hébergeant différentes fusions MLL telles que les cellules MV4;11, RS4;11, MOLM13 et NOMO1 avec une IC50 de 15-192 nM. De manière cohérente, il abolit complètement le potentiel de formation de colonies des leucémies induites par fusion MLL (MOLM13) mais pas des leucémies induites par l'activation de la tyrosine kinase (K562). I-BET151 montre également une efficacité puissante dans les essais en culture liquide et clonogéniques utilisant des progéniteurs murins primaires transformés avec MLL-ENL ou MLL-AF9. Le traitement avec ce composé induit significativement l'apoptose et un arrêt G0/G1 prononcé dans les lignées cellulaires de fusion MLL conduites par des fusions MLL distinctes (MOLM13 et MV4;11 contenant MLL-AF9 et MLL-AF4, respectivement) mais pas les cellules K562, probablement en raison de l'inhibition de la transcription de BCL2, C-MYC et CDK6 en bloquant le recrutement des composants BRD3/4, PAFc et SEC au site d'initiation de la transcription (TSS).
Essai kinase
Essai de déplacement de ligand par anisotropie de fluorescence (FP)
Tous les composants sont dissous dans un tampon de composition 50 mM HEPES pH 7,4, 150 mM NaCl et 0,5 mM CHAPS avec des concentrations finales de BRD 2/3/4 de 75 nM, ligand fluorescent de 5 nM. 10 μL de ce mélange réactionnel sont ajoutés à l'aide d'un micro multidrop dans des puits contenant 100 nL de diverses concentrations de I-BET151 (GSK1210151A) ou de véhicule DMSO (1% final) dans une plaque de microtitration Greiner 384 puits noire à faible volume et équilibrés dans l'obscurité pendant 60 minutes à température ambiante. L'anisotropie de fluorescence est lue dans Envision (lex = 485 nm, lEM = 530 nm; Dichroïque = 505 nM).
In vivo
I-BET151 (GSK1210151A), administré à 30 mg/kg/jour, inhibe significativement la croissance tumorale des leucémies murines MLL-AF9 et humaines MLL-AF4 chez la souris, et procure un bénéfice de survie marqué.
Références

Applications (Applications)

Méthodes Biomarqueurs Images PMID
Western blot α-SMA / Fibronectin / Collagen-1 FoxM1 / AURKB / Survivin / cyclin B / PLK1 HP1α / HP1β / HP1γ
S2780-WB1
27732564