Name: Birabresib (OTX015)
Brand: Selleck Chemicals
SKU: S7360
Rating: 5 (73 reviews)

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Batch: Zuiverheid: 99.81%

99.81

Gerelateerde doelwitten	HDAC JAK Histone Methyltransferase PKC PARP HIF PRMT EZH2 AMPK Histone Acetyltransferase
Overig BET Inhibitoren	Pelabresib (CPI-0610) ZEN-3694 (BET-IN-19) Molibresib (I-BET-762) Mivebresib (ABBV-075) INCB054329 I-BET151 (GSK1210151A) Apabetalone (RVX-208) AZD5153 6-hydroxy-2-naphthoic acid CPI-203 I-BRD9

Celkweek, behandeling & werkzame concentratie

Cellijnen	Assaytype	Concentratie	Incubatietijd	Activiteitsbeschrijving	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
Klik om meer experimentele gegevens over cellijnen te bekijken

Chemische informatie, opslag en stabiliteit

Molecuulgewicht	491.99	Formule	C₂₅H₂₂ClN₅O₂S	Opslag (vanaf de datum van ontvangst)	3 jaar-20°Cpoeder
CAS-nr.	202590-98-5	SDF downloaden		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	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

Oplosbaarheid

In vitro
Batch:

DMSO : 98 mg/mL (199.19 mM)
(Met vocht verontreinigd DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Ethanol : 11 mg/mL

Water : Insoluble

Molariteitscalculator

Massa	Concentratie	Volume	Molecuulgewicht
=	×	×

Verdunningscalculator Molecuulgewichtcalculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo formulatiecalculator (heldere oplossing)

Stap 1: Voer onderstaande informatie in (Aanbevolen: een extra dier om rekening te houden met verlies tijdens het experiment)

Dosering: mg/kg Gemiddeld gewicht van dieren: g Doseervolume per dier:μL Aantal dieren:

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 de sectie oplosbaarheid.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berekeningsresultaten:

Werkconcentratie: mg/ml;

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

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toeμL PEG300, mengen en verhelderen, daarna toevoegenμL Tween 80, mengen en verhelderen, daarna toevoegen μL ddH₂O, mengen en verhelderen.

Methode voor het bereiden van in vivo formulering: Neem μL DMSO moedervloeistof, voeg daarna toe μL Maïsolie, mengen en verhelderen.

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. Fysieke methoden zoals vortexen, ultrasoon of een warmwaterbad kunnen worden gebruikt om het oplossen te bevorderen.

Werkingsmechanisme

Kenmerken	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) remt de binding van BRD2, BRD3 en BRD4 aan AcH4 met IC50 variërend van 92 tot 112 nM, en remt de groei van een verscheidenheid aan menselijke kankercellijnen met GI50 variërend van 60 tot 200 nM. Het resulteert in een snelle down-regulatie van c-MYC expressie, en vertoont synergistische anti-proliferatieve effecten in combinatie met ALK-remmers in ALKpos ALCL cellijnen.
Kinase Assay	TR-FRET-assay
Kinase Assay	Om de binding van Birabresib (OTX015) aan BRD2, BRD3 en BRD4 te beoordelen, worden BRD-expressie CHO-cellysaat (van CHO-cellen getransfecteerd met expressieplasmiden voor Flag-getagd BRD2, BRD3 of BRD4 of alleen vector), europium-geconjugeerde anti-Flag antilichaam, XL-665-geconjugeerde streptavidine en gebiotinyleerd it gedurende 0,2 tot 2 uur bij kamertemperatuur geïncubeerd. Fluorescentie wordt gemeten door TR-FRET met behulp van een EnVision 2103 Multilabel Reader en EC50 voor binding wordt berekend door niet-lineaire regressie met behulp van PRISM versie 5.02.
In vivo	Birabresib (OTX015) remt de groei van Ty82 BRD-NUT midline carcinoomtumoren in naakte muizen significant met 79% bij 100 mg/kg qd en 61% bij 10 mg/kg bid, respectievelijk, wanneer oraal (p.o.) toegediend.
Referenties	[1] http://mct.aacrjournals.org/content/12/11_Supplement/C244.short [2] http://mct.aacrjournals.org/content/12/11_Supplement/A219.short

Toepassingen

Methoden	Biomarkers	Afbeeldingen	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		26051217
Immunofluorescence	BRD4 Vimentin		28042144

Informatie over klinische proeven

(gegevens van https://clinicaltrials.gov, bijgewerkt op 2024-05-22)

NCT-nummer	Werving	Aandoeningen	Sponsor/medewerkers	Startdatum	Fasen
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

Technische ondersteuning

Gebruiksaanwijzing

Tel: +1-832-582-8158 Ext:3

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Birabresib (OTX015) BET remmer

Chemische structuur

Molecuulgewicht: 491.99