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Birabresib (OTX015) BET Inibitore

N. Cat.: S7360

Birabresib (OTX015, MK 8628) è un potente inibitore di BET bromodomain con EC50 che varia da 10 a 19 nM per BRD2, BRD3 e BRD4 in saggi senza cellule. Inibisce l'espressione dei geni bersaglio di Nuclear receptor binding SET domain protein 3 (NSD3).
Birabresib (OTX015) BET Inibitore Chemical Structure

Struttura chimica

Peso molecolare: 491.99

Vai a

Controllo Qualità (Quality Control)

Lotto: Purezza: 99.81%
99.81

Coltura cellulare, trattamento e concentrazione di lavoro
(Cell Culture, Treatment & Working Concentration)

Linee cellulari Tipo di saggio Concentrazione Tempo di incubazione Formulazione Descrizione dell'attività PMID
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=0.004μM. 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=0.0054μM. 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=0.006μM. 26080064
MM1S Antiproliferative assay 72 hrs Antiproliferative activity against human MM1S cells after 72 hrs by CCK8 or SRB assay, IC50=0.0063μM. 31490070
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=0.0107μM. 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=0.0109μM. 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=0.0166μM. 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=0.0166μM. 26080064
MV4-11 Antiproliferative assay 4 days Antiproliferative activity against human MV4-11 cells assessed as cell growth inhibition after 4 days by CCK8 assay, IC50=0.0176μM. 31461688
MM1S Antiproliferative assay 4 days Antiproliferative activity against human MM1S cells assessed as cell growth inhibition after 4 days by CCK8 assay, IC50=0.0227μM. 31461688
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=0.0255μM. 26080064
THP1 Antiproliferative assay Antiproliferative activity against human THP1 cells, IC50=0.033μM. 28939121
BL21(DE3) Function assay 4 hrs Displacement of 5-FITC labelled (+)-JQ1 from His6-tagged human BRD4 bromodomain 1 expressed in Escherichia coli BL21(DE3) )-codon plus-RIL cells incubated for 4 hrs in dark condition by fluorescence anisotropy binding assay, IC50=0.0343μM. 31490070
MV4-11 Antiproliferative assay 72 hrs Antiproliferative activity against human MV4-11 cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay, IC50=0.0463μM. 32208600
TY82 Antiproliferative assay Antiproliferative activity against human TY82 cells, IC50=0.067μM. 28939121
insect cells Function assay Inhibition of recombinant full length human N-terminal His6-tagged BRD4 (2 to 1362 residues) expressed in baculovirus infected insect cells using histone H4 peptide as substrate by alpha screen assay, IC50=0.092μM. 30529546
LNCAP Antiproliferative assay Antiproliferative activity against human LNCAP cells, IC50=0.1114μM. 29758518
Kasumi-1 Antiproliferative assay 72 hrs Antiproliferative activity against human Kasumi-1 cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay, IC50=0.135μM. 32208600
MM1S Antiproliferative assay 72 hrs Antiproliferative activity against human MM1S cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay, IC50=0.137μM. 32208600
RS4:11 Antiproliferative assay 72 hrs Antiproliferative activity against human RS4:11 cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay, IC50=0.416μM. 32208600
MV4-11 Cell cycle assay 125 nM 24 hrs Cell cycle arrest in human MV4-11 cells assessed as increase in accumulation at G1-phase at 125 nM measured after 24 hrs by propidium iodide staining based flow cytometry 32208600
MV4-11 Function assay 500 nM 6 to 24 hrs Inhibition of BRD4 in human MV4-11 cells assessed as reduction in c-Myc expression at 500 nM measured after 6 to 24 hrs by Western blot analysis 32208600
MV4-11 Function assay 31.25 to 125 nM 6 hrs Inhibition of BRD4 in human MV4-11 cells assessed as reduction in c-Myc mRNA level at 31.25 to 125 nM measured after 6 hrs by SYBR green dye based RT-qPCR analysis 32208600
MV4-11 Function assay 31.25 to 125 nM 6 hrs Inhibition of BRD4 in human MV4-11 cells assessed as reduction in BCL2 mRNA level at 31.25 to 125 nM measured after 6 hrs by SYBR green dye based RT-qPCR analysis 32208600
MV4-11 Function assay 31.25 to 125 nM 6 hrs Inhibition of BRD4 in human MV4-11 cells assessed as reduction in CDK6 mRNA level at 31.25 to 125 nM measured after 6 hrs by SYBR green dye based RT-qPCR analysis 32208600
TY82 Antiproliferative assay 72 hrs Antiproliferative activity against human TY82 cells after 72 hrs by CCK8 or SRB assay 31490070
MV4-11 Function assay 10 to 100 nM 24 hrs Inhibition of BRD4 in human MV4-11 cells assessed as reduction in c-Myc mRNA level at 10 to 100 nM after 24 hrs by real time qPCR analysis 31490070
MV4-11 Antiproliferative assay 72 hrs Antiproliferative activity against human MV4-11 cells after 72 hrs by CCK8 or SRB assay 31490070
MV4-11 Apoptosis assay 24 hrs Induction of apoptosis in human MV4-11 cells after 24 hrs by Annexin V staining based assay 31490070
RKO Cell cycle assay 100 nM 24 hrs Induction of cell cycle arrest in human RKO cells assessed as increase in accumulation at G1 phase at 100 nM after 24 hrs by propidium iodide staining based flow cytometric analysis 31490070
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Informazioni chimiche, conservazione e stabilità (Chemical Information, Storage & Stability)

Peso molecolare 491.99 Formula

C25H22ClN5O2S

 Conservazione (Dalla data di ricezione)
N. CAS 202590-98-5 Scarica SDF Conservazione delle soluzioni stock

Sinonimi MK 8628 Smiles CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NC4=CC=C(C=C4)O)C5=CC=C(C=C5)Cl)C

Solubilità (Solubility)

In vitro
Lotto:

DMSO : 98 mg/mL (199.19 mM)
(Il DMSO contaminato da umidità può ridurre la solubilità. Utilizzare DMSO fresco e anidro.)

Ethanol : 11 mg/mL

Water : Insoluble

Calcolatore di Molarità

Massa Concentrazione Volume Peso molecolare
Calcolatore di Diluizione Calcolatore del Peso Molecolare

In vivo
Lotto:

Calcolatore di formulazione in vivo (Soluzione chiara)

Passo 1: Inserire le informazioni di seguito (Consigliato: Un animale aggiuntivo per tenere conto della perdita durante l'esperimento)

mg/kg g μL

Passo 2: Inserire la formulazione in vivo (Questo è solo il calcolatore, non la formulazione. Contattateci prima se non c'è una formulazione in vivo nella sezione Solubilità.)

% DMSO % % Tween 80 % ddH2O
%DMSO %

Risultati del calcolo:

Concentrazione di lavoro: mg/ml;

Metodo per preparare il liquido master di DMSO: mg farmaco predissolto in μL DMSO ( Concentrazione del liquido master mg/mL, Vi preghiamo di contattarci prima se la concentrazione supera la solubilità del DMSO del lotto del farmaco. )

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungereμL PEG300, mescolare e chiarire, quindi aggiungereμL Tween 80, mescolare e chiarire, quindi aggiungere μL ddH2O, mescolare e chiarire.

Metodo per preparare la formulazione in vivo: Prendere μL DMSO liquido master, quindi aggiungere μL Olio di mais, mescolare e chiarire.

Nota: 1. Si prega di assicurarsi che il liquido sia limpido prima di aggiungere il solvente successivo.
2. Assicurarsi di aggiungere il/i solvente/i in ordine. È necessario assicurarsi che la soluzione ottenuta, nell'aggiunta precedente, sia una soluzione limpida prima di procedere all'aggiunta del solvente successivo. Metodi fisici come il vortex, gli ultrasuoni o il bagno d'acqua calda possono essere utilizzati per facilitare la dissoluzione.

Meccanismo d'azione (Mechanism of Action)

Caratteristiche
Orally bioavailable BRD2/3/4-selective inhibitor that has been tested in Phase I clinical trials for treatment of Haematological Malignancies.
Targets/IC50/Ki
BRDs
(Cell-free assay)
10-19 nM(EC50)
In vitro
Birabresib (OTX015) inhibits the binding of BRD2, BRD3, and BRD4 to AcH4 with IC50 ranging from 92 to 112 nM, and inhibits the growth of a variety of human cancer cell lines with GI50 ranging from 60 to 200 nM. It results in rapid down-regulation of c-MYC expression, and shows synergistic anti-proliferative effects in combination with ALK inhibitors in ALKpos ALCL cell lines.
Saggio chinasico
Saggio TR-FRET
Per valutare il legame di Birabresib (OTX015) a BRD2, BRD3 e BRD4, il lisato cellulare di CHO che esprime BRD (da cellule CHO trasfettate con plasmidi di espressione per BRD2, BRD3 o BRD4 con tag Flag o solo vettore), l'anticorpo anti-Flag coniugato con europio, la streptavidina coniugata con XL-665 e il biotina sono incubati a temperatura ambiente per 0,2-2 ore. La fluorescenza viene misurata tramite TR-FRET utilizzando un lettore multietichetta EnVision 2103 e l'EC50 per il legame viene calcolata mediante regressione non lineare utilizzando PRISM versione 5.02.
In vivo
Birabresib (OTX015) significantly inhibits the growth of Ty82 BRD-NUT midline carcinoma tumors in nude mice by 79% at 100 mg/kg qd and 61% at 10 mg/kg bid, respectively, when administered orally (p.o.).
Riferimenti

Applicazioni (Applications)

Metodi Biomarcatori Immagini PMID
Western blot BRD4 c-Myc JAK2 / p-STAT5 / STAT5 / p-STAT3 / c-Myc / PIM1 / CDK6 / HEXIM1 / p27 / p21 / Bcl-xL / γH2AX ZO-1 / Vimentin
S7360-WB1
26051217
Immunofluorescence BRD4 Vimentin
S7360-IF1
28042144

Informazioni sullo studio clinico (Clinical Trial Information)

(dati da https://clinicaltrials.gov, aggiornato il 2024-05-22)

Numero NCT Reclutamento Condizioni Sponsor/Collaboratori Data di inizio Fasi
NCT02698176 Terminated
NUT Midline Carcinoma (NMC)|Triple Negative Breast Cancer (TNBC)|Non-small Cell Lung Cancer (NSCLC)|Castration-resistant Prostate Cancer (CRPC)
Merck Sharp & Dohme LLC
 May 4 2016 Phase 1
NCT02698189 Terminated
AML Including AML de Novo and AML Secondary to MDS|DLBCL
Merck Sharp & Dohme LLC
 May 19 2016 Phase 1
NCT02296476 Terminated
Glioblastoma Multiforme
Oncoethix GmbH a subsidiary of Merck & Co. Inc. (Rahway New Jersey USA)
 October 29 2014 Phase 2
NCT02259114 Completed
NUT Midline Carcinoma|Triple Negative Breast Cancer|Non-small Cell Lung Cancer With Rearranged ALK Gene/Fusion Protein or KRAS Mutation|Castrate-resistant Prostate Cancer|CRPC|Pancreatic Ductal Adenocarcinoma
Oncoethix GmbH a subsidiary of Merck & Co. Inc. (Rahway New Jersey USA)
 October 23 2014 Phase 1
NCT01713582 Completed
Acute Myeloid Leukemia|Diffuse Large B-cell Lymphoma|Acute Lymphoblastic Leukemia|Multiple Myeloma
Oncoethix GmbH a subsidiary of Merck & Co. Inc. (Rahway New Jersey USA)
 December 14 2012 Phase 1