endast för forskning

Quisinostat (JNJ-26481585) Dihydrochloride HDAC Hämmare

Name: Quisinostat (JNJ-26481585) Dihydrochloride
Brand: Selleck Chemicals
SKU: S1096
Rating: 5 (62 reviews)

Kat.nr.: S1096

Quisinostat (JNJ-26481585) 2HCl är en ny andra generationens HDAC-hämmare med högst potens för HDAC1 med IC50 på 0,11 nM i en cellfri analys, måttlig potens mot HDAC2, 4, 10 och 11; större än 30 gånger selektivitet mot HDAC3, 5, 8 och 9 och lägst potens mot HDAC6 och 7. Fas 2.

Quisinostat (JNJ-26481585) Dihydrochloride HDAC Hämmare Chemical Structure

Kemisk struktur

Molekylvikt: 467.39

Hoppa till

Kvalitetskontroll (Quality Control)

Batch: Renhet: 99.62%

99.62

Relaterade mål	JAK BET Histone Methyltransferase PKC PARP HIF PRMT EZH2 AMPK Sirtuin
Övrigt HDAC Inhibitorer	ITF-2357 (Givinostat) Hydrochloride Monohydrate Fimepinostat (CUDC-907) Trichostatin A (TSA) Entinostat (MS-275) RGFP966 Tubastatin A Hydrochloride Tubastatin A Mocetinostat (MGCD0103) Ricolinostat (ACY-1215) PCI-34051

Cellodling, behandling & arbetskoncentration
(Cell Culture, Treatment & Working Concentration)

Cellinjer	Analystyp	Koncentration	Inkubationstid	Aktivitetsbeskrivning	PMID
A549 cells	Cell viability assay		24, 48, or 72 h	the IC50 values of cells for 48 and 72 h of quisinostat treatment were 82.4 and 42.0 nM, respectively.	27423454
RH30 cells	Function assay	15 nM	24 h and 30 h	GSK690 and JNJ-26481585 cooperated to induce cleavage of the initiator caspase-9 into its active p35 and p37 fragments and of the effector caspase-3 into its active p12 and p17 fragments	28617441
RD cells	Function assay	15 nM	24 h and 30 h	GSK690 and JNJ-26481585 cooperated to induce cleavage of the initiator caspase-9 into its active p35 and p37 fragments and of the effector caspase-3 into its active p12 and p17 fragments	28617441
HepG2	Cell viability assay	5, 10, 20, 40, 80, 160 and 320 nM	24, 48, 72 h	The IC50 values of cells for quisinostat treatment at 48 and 72 h were 81.2 and 30.8 nM, respectively.	28849080
HuT78	Function assay	10 nM		increases the level of acetylated lysine K10 of histone H3	30012418
Sf9	Function assay			Inhibition of full length recombinant human HDAC1 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.00011 μM.	27606546
Sf9	Function assay			Inhibition of full length recombinant human HDAC2 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.00033 μM.	27606546
Sf9	Function assay			Inhibition of full length recombinant human HDAC3/NCOR2 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.00486 μM.	27606546
HUT78	Function assay		18 hrs	Pro-apoptotic activity in human HUT78 cells after 18 hrs by caspase-Glo 3/7 assay, EC50 = 0.0065 μM.	30122227
BL21 (DE3)	Function assay			Binding affinity to human His-thioredoxin-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells by ITC method, Kd = 0.0227 μM.	30347148
BL21 (DE3)	Function assay			Binding affinity to Schistosoma mansoni His-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells by ITC method, Kd = 0.0284 μM.	30347148
BL21 (DE3)	Function assay			Inhibition of human His-thioredoxin-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.0644 μM.	30347148
Sf9	Function assay			Inhibition of full length recombinant human HDAC6 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis, IC50 = 0.0768 μM.	27606546
BL21 (DE3)	Function assay			Inhibition of human His-thioredoxin-tagged HDAC8 mL6 mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.093 μM.	30347148
BL21 (DE3)	Function assay			Inhibition of human His-thioredoxin-tagged HDAC8 mL1/mL6 mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.094 μM.	30347148
BL21 (DE3)	Function assay			Inhibition of human His-thioredoxin-tagged HDAC8 mL6/L179I mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.169 μM.	30347148
BL21 (DE3)	Function assay			Inhibition of human His-thioredoxin-tagged HDAC8 mL1/mL6/L179I mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.217 μM.	30347148
BL21 (DE3)	Function assay			Inhibition of Schistosoma mansoni His-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method, IC50 = 0.3034 μM.	30347148
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for TC32 cells	29435139
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
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
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
BT-12	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for BT-12 cells	29435139
DAOY	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for DAOY 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
SK-N-SH	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SK-N-SH cells	29435139
Rh41	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh41 cells	29435139
A673	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for A673 cells)	29435139
Rh30	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh30 cells	29435139
MG 63 (6-TG R)	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for MG 63 (6-TG R) cells	29435139
fibroblast cells	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for control Hh wild type fibroblast cells	29435139
Rh30	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh30 cells	29435139
U-2 OS	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for U-2 OS cells	29435139
OHS-50	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for OHS-50 cells	29435139
SK-N-SH	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for SK-N-SH cells	29435139
Rh41	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh41 cells	29435139
RD	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for RD cells	29435139
Daoy	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for Daoy cells	29435139
TC32	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for TC32 cells	29435139
MG 63 (6-TG R)	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for MG 63 (6-TG R) 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
NB1643	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for NB1643 cells	29435139
SJ-GBM2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for SJ-GBM2 cells	29435139
Rh18	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Rh18 cells	29435139
Saos-2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Confirmatory screen for Saos-2 cells	29435139
SJ-GBM2	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for SJ-GBM2 cells	29435139
RD	qHTS assay			qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Orthogonal 3D viability screen for RD cells	29435139
Klicka för att visa mer experimentella data för cellinjer

Kemisk information, lagring & stabilitet (Chemical Information, Storage & Stability)

Molekylvikt	467.39	Formel	C₂₁H₂₈Cl₂N₆O₂	Lagring (från mottagningsdatumet)	3 år-20°Cpulver
CAS-nr	875320-31-3	--		Lagring av stamlösningar	1 år-80°Ci lösningsmedel 1 månad-20°Ci lösningsmedel
Synonymer	N/A			Smiles	CN1C=C(C2=CC=CC=C21)CNCC3CCN(CC3)C4=NC=C(C=N4)C(=O)NO.Cl.Cl

Löslighet (Solubility)

In vitro
Batch:

DMSO : 79 mg/mL (169.02 mM)
(Fuktkontaminerad DMSO kan minska lösligheten. Använd färk, vattenfri DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molaritetsräknare

Massa	Koncentration	Volym	Molekylvikt
=	×	×

Utspädningsräknare Molekylviktsräknare

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.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O Validerad av Selleck-laboratorier. Om du behöver justeringar av denna formulering, kontakta vårt säljteam för skräddarsydd testning.	4.000mg/ml (8.56mM)	Taking the 1 mL working solution as an example, add 50 μL of 80 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Clear solution	5% DMSO 1 95% Corn oil Validerad av Selleck-laboratorier. Om du behöver justeringar av denna formulering, kontakta vårt säljteam för skräddarsydd testning.	0.500mg/ml (1.07mM)	Taking the 1 mL working solution as an example, add 50 μL of 10 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.

In vivo-formuleringsräknare (Klar lösning)

Steg 1: Ange information nedan (Rekommenderas: Ett extra djur för att ta hänsyn till förluster under experimentet)

Dosering: mg/kg Djurens medelvikt: g Doseringsvolym per djur:μL Antal djur:

Steg 2: Ange in vivo-formuleringen (Detta är endast räknaren, inte formuleringen. Vänligen kontakta oss först om det inte finns någon in vivo-formulering i löslighetsavsnittet.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Beräkningsresultat:

Arbetskoncentration: mg/ml;

Metod för att bereda DMSO-stamlösning: mg substans förlöst i μL DMSO ( Stamlösningskoncentration mg/mL, Vänligen kontakta oss först om koncentrationen överskrider DMSO-lösligheten för denna batch av substansen. )

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedanμL PEG300, blanda och klarna, tillsätt sedanμL Tween 80, blanda och klarna, tillsätt sedan μL ddH₂O, blanda och klarna.

Metod för att bereda in vivo-formulering: Ta μL DMSO stamlösning, tillsätt sedan μL Majsolja, blanda och klarna.

Obs: 1. Se till att vätskan är klar innan du tillsätter nästa lösningsmedel.
2. Se till att tillsätta lösningsmedlet/lösningsmedlen i ordning. Du måste se till att lösningen som erhålls i föregående tillsats är en klar lösning innan du fortsätter att tillsätta nästa lösningsmedel. Fysiska metoder som vortex, ultraljud eller varmt vattenbad kan användas för att underlätta upplösningen.

Verkningsmekanism (Mechanism of Action)

Egenskaper	An orally bioavailable, second-generation, hydroxamic acid-based HDAC inhibitor.
Targets/IC₅₀/Ki	HDAC1 (Cell-free assay) 0.11 nM HDAC2 (Cell-free assay) 0.33 nM HDAC11 (Cell-free assay) 0.37 nM HDAC10 (Cell-free assay) 0.46 nM HDAC4 (Cell-free assay) 0.64 nM HDAC5 (Cell-free assay) 3.69 nM HDAC8 (Cell-free assay) 4.26 nM HDAC3 (Cell-free assay) 4.86 nM
In vitro	JNJ-26481585 exhibits broad spectrum antiproliferative activity in solid and hematologic cancer cell lines, such as all lung, breast, colon, prostate, brain, and ovarian tumor cell lines, with IC50 ranging from 3.1-246 nM, which is more potent than R306465, CRA-24781, or mocetinostat in various human cancer cell lines tested. A recent study shows that JNJ-26481585 promotes myeloma cell death at low nanomolar concentrations by resulting in Mcl-1 depletion and Hsp72 induction.
Kinasanalys	HDAC-aktivitetsanalyser
Kinasanalys	I samtliga fall uttrycks fullängds-HDAC-proteiner med hjälp av bakulovirusinfekterade Sf9-celler. Dessutom samexpresseras HDAC3 som ett komplex med humant NCOR2. För att bedöma aktiviteten hos HDAC1-innehållande cellulära komplex inkuberas immunoprecipiterade HDAC1-komplex med ett [³H]acetyl-märkt fragment av histon H4-peptid [biotin-(6-aminohexanoic)Gly-Ala-(acetyl[3H])Lys-Arg-His-Arg-Lys-Val-NH2] i en total volym av 50 μL enzymanalysbuffert (25 mM HEPES (pH 7.4), 1 M sackaros, 0.1 mg/mL BSA och 0.01% (v/v) Triton X-100). Inkubationen utförs i 45 minuter vid 37 °C (immunoprecipitat) eller 30 minuter vid rumstemperatur. Före tillsats av substrat tillsätts HDAC-hämmare i ökande koncentrationer och förinkuberas i 10 minuter vid rumstemperatur. Efter inkubation släcks reaktionen med 35 μL stoppbuffert (1 M HCl och 0.4 M ättiksyra). Frisläppt [³H]ättiksyra extraheras med 800 μL etylacetat och kvantifieras genom scintillationsräkning. Lika mängder HDAC1 immunoprecipiteras vilket indikeras av Western blot-analys. HDAC1-aktivitetsresultaten presenteras som medelvärde ± SD av tre oberoende experiment på ett enda lysat.
In vivo	In an HDAC1-responsive A2780 ovarian tumor screening model, JNJ-26481585 dosing at its maximal tolerated dose (10 mg/kg i.p. and 40 mg/kg p.o.) for 3 days leads to an HDAC1-regulated fluorescence , which predicts tumor growth inhibition. Furthermore, JNJ-26481585 also shows more potent inhibitory effects on the growth of C170HM2 colorectal liver metastases.
Referenser	[1] https://pubmed.ncbi.nlm.nih.gov/19861438/ [2] https://pubmed.ncbi.nlm.nih.gov/20331455/

Applikationer (Applications)

Metoder	Biomarkörer	Bilder	PMID
Western blot	HDAC1 / HDAC2 / HDAC4 p21 / CDK2 / CDK4 / CDK6 / Cyclin D1 / Cyclin E1 / Cyclin A2 Caspase-3/ Cleaved caspase-3 / caspase-9 / Cleaved caspase-9 / PARP / Cleaved PARP / Bcl-xl / Bcl2 / Bax / Survivin PI3K-p110 / PI3K-p85 / p-AKT / JNK / p-JNK / p-c-Jun		30443188
Growth inhibition assay	Cell viability		30443188

Klinisk prövningsinformation (Clinical Trial Information)

(data från https://clinicaltrials.gov, uppdaterad den 2024-05-22)

NCT-nummer	Rekrytering	Tillstånd	Sponsor/Samarbetspartners	Startdatum	Faser
NCT02948075	Completed	Ovarian Cancer	NewVac LLC\|Janssen Pharmaceutica N.V. Belgium	September 2015	Phase 2
NCT01464112	Completed	Multiple Myeloma	Janssen Research & Development LLC	September 16 2011	Phase 1
NCT00676728	Terminated	Advanced or Refractory Leukemia\|Myelodysplastic Syndromes	Johnson & Johnson Pharmaceutical Research & Development L.L.C.	December 2008	Phase 1
NCT00677105	Completed	Lymphoma\|Neoplasms	Johnson & Johnson Pharmaceutical Research & Development L.L.C.\|Janssen Pharmaceutica N.V. Belgium	August 2007	Phase 1

Vanliga frågor (Frequently Asked Questions)

Fråga 1:
I was thinking of resuspending it in 10% hydroxy-propyl-β-cyclodextrin, 25mg/ml mannitol, in sterile water (final pH 8.7). Is this a good vehicle to use? What is the solubility of this compound in such a vehicle?

Svar:
This vehicle can be used for in vivo studies. The following papers also used this vehicle: 1. http://www.nature.com/leu/journal/v23/n10/full/leu2009121a.html; 2. http://cancerres.aacrjournals.org/content/69/13/5307.long (The solvent contains 10% hydroxypropyl-β-cyclodextrin, 0.8% HCl (0.1 N), 0.9 % NaOH (0.1 N), 3.4% mannitol and pyrogen-free water). Its solubility is 2mg/ml.

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):