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Regorafenib (BAY-734506) Monohydrate VEGFR remmer

Name: Regorafenib (BAY-734506) Monohydrate
Brand: Selleck Chemicals
SKU: S5077
Rating: 5 (50 reviews)

Cat.nr.S5077

Regorafenib (BAY-734506, Fluoro-sorafenib, Resihance, Stivarga, regorafaenib monohydrate) Monohydraat is een nieuwe orale multikinase-remmer met IC50-waarden van 13, 4,2, 46, 22, 7, 1,5, 2,5, 28, 19 nM voor respectievelijk VEGFR1, murine VEGFR2, murine VEGFR3, PDGFR-β, Kit (c-Kit), RET (c-RET), RAF-1, B-RAF en B-RAF(V600E).

Regorafenib (BAY-734506) Monohydrate VEGFR remmer Chemical Structure

Chemische structuur

Molecuulgewicht: 500.83

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Kwaliteitscontrole

Batch: Zuiverheid: 99.99%

99.99

Gerelateerde doelwitten	EGFR PDGFR FGFR c-Met Src MEK CSF-1R FLT3 HER2 c-Kit
Overig VEGFR Inhibitoren	SAR131675 SU 5402 Cediranib (AZD2171) Vatalanib (PTK787) 2HCl Anlotinib (AL3818) Dihydrochloride Linifanib (ABT-869) Apatinib (YN968D1) Apatinib (YN968D1) mesylate Ki8751 ZM 323881 HCl

Celkweek, behandeling & werkzame concentratie

Cellijnen	Assaytype	Incubatietijd	Activiteitsbeschrijving	PMID
GISTT1	Cytotoxicity assay	72 hrs	Cytotoxicity against human GISTT1 cells assessed as cell growth inhibition after 72 hrs by CellTiterGlo assay, GI50=0.13μM	28991465
GISTT1	Cytotoxicity assay	72 hrs	Cytotoxicity against human GISTT1 cells harboring KIT T670I mutant assessed as cell growth inhibition after 72 hrs by CellTiterGlo assay, GI50=0.38μM	28991465
GISTT1	Cytotoxicity assay	72 hrs	Cytotoxicity against human GISTT1 cells harboring KIT D816E mutant assessed as cell growth inhibition after 72 hrs by CellTiterGlo assay, GI50=1.35μM	28991465
GIST430	Cytotoxicity assay	72 hrs	Cytotoxicity against human GIST430 cells harboring KIT V654A mutant assessed as cell growth inhibition after 72 hrs by CellTiterGlo assay, GI50=3μM	28991465
DAOY	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for DAOY 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
A673	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for A673 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
BT-37	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-37 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
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
Saos-2	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Saos-2 cells	29435139
NB1643	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for NB1643 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
BT-12	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for BT-12 cells	29435139
Rh18	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for Rh18 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
RD	qHTS assay		qHTS of pediatric cancer cell lines to identify multiple opportunities for drug repurposing: Primary screen for RD 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
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.021μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of TEL-fused PDGFRbeta (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.029μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and D816H mutant and T670I mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.033μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and A829P mutant and Y823D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.047μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and N822K mutant and Y823D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.049μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of TEL-fused PDGFRalpha (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.051μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and D820A mutant and D820A mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.063μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and Y823D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.094μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit V560D mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.108μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of KDR (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.114μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 9 AY502 to 503 insertion mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.114μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and V654A mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.231μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (557 to 558 residues) and D816H mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.29μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of PDGFRalpha V561D/D842V mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.522μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit V560D/V654A mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.549μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 9 AY502 to 503 insertion and D816 mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.833μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit V560D/D816H mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.834μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 11 deletion (560 to 578 residues) mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=0.943μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit exon 9 AY502 to 503 insertion and V654 mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=1.27μM	30204441
BA/F3	Function assay	72 hrs	Inhibition of Kit D816V mutant (unknown origin) transfected in mouse BA/F3 cells assessed as inhibition of cell growth incubated for 72 hrs by MTS assay, GI50=2.371μM	30204441
BA/F3	Cytotoxicity assay	72 hrs	Cytotoxicity in mouse parental BA/F3 cells incubated for 72 hrs by MTS assay, GI50=9.953μM	30204441
Sf9	Function assay		Inhibition of human N-terminal GST tagged VEGFR-2 expressed in baculovirus infected Sf9 cells using poly (Glu,Tyr) 4:1 as substrate in presence of ATP by Kinase-Glo luminescence assay, IC50=0.005μM	31284081
Sf9	Function assay	4 hrs	Inhibition of wild type recombinant GST-tagged FLT3 (Y567 to S993 residues) (unknown origin) expressed in baculovirus infected Sf9 insect cells using Her2 peptide as substrate measured after 4 hrs in presence of ATP by Kinase-Glo Plus reagent-based lumine, IC50=0.082μM	31721578
Sf9	Function assay	150 mins	Inhibition of recombinant N-terminal 6x-His-tagged c-KIT (547 to 935 residues)/(694 to 753 residues deletion) (unknown origin) expressed in baculovirus infected Sf9 insect cells using poly (Glu,Tyr) 4:1 as substrate measured after 150 mins in presence of , IC50=0.116μM	31721578
GISTT1	Antiproliferative assay	72 hrs	Antiproliferative activity against human GISTT1 cells harboring heterozygous deletion mutation at C-kit exon 11 assessed as cell growth inhibition after 72 hrs by CellTiter 96 AQueous One Solution Cell Proliferation assay, GI50=0.119μM	31721578
GIST882	Antiproliferative assay	144 hrs	Antiproliferative activity against human GIST882 cells harboring c-KIT exon 13 homozygous primary K642E mutant assessed as cell growth inhibition after 144 hrs by methylene blue staining based assay, GI50=0.285μM	31721578
GIST48	Antiproliferative assay	120 hrs	Antiproliferative activity against human GIST48 cells harboring c-KIT exon 11 homozygous primary missense V560D mutant and exon 17 heterozygous secondary D820A mutant assessed as cell growth inhibition after 120 hrs by methylene blue staining based assay, GI50=0.785μM	31721578
Caco-2	Toxicity assay	48 hrs	Toxicity against Caco-2 cells determined at 48 hours by intracellular ATP concentration using the CellTiter-Glo Luminescent Cell Viability Assay, CC50=0.97μM	ChEMBL
Caco-2	Function assay	48 hrs	Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells after 48 hours by high content imaging, IC50=1.67μM	ChEMBL
VERO-E6	Toxicity assay	48 hrs	Toxicity CC50 against VERO-E6 cells determined at 48 hours by high content imaging (same conditions as 2_LEY without exposure to 0.01 MOI SARS CoV-2 virus), CC50=8.31μM	ChEMBL
VERO-E6	Function assay	48 hrs	Determination of IC50 values for inhibition of SARS-CoV-2 induced cytotoxicity of VERO-E6 cells after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging, IC50=24.95μM	ChEMBL
Klik om meer experimentele gegevens over cellijnen te bekijken

Chemische informatie, opslag en stabiliteit

Molecuulgewicht	500.83	Formule	C₂₁H₁₅ClF₄N₄O₃.H₂O	Opslag (vanaf de datum van ontvangst)	3 jaar-20°Cpoeder
CAS-nr.	1019206-88-2	--		Opslag van stamoplossingen	1 jaar-80°Cin oplosmiddel 1 maand-20°Cin oplosmiddel
Synoniemen	Fluoro-sorafenib, Resihance, Stivarga, regorafaenib monohydrate			Smiles	CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F.O

Oplosbaarheid

In vitro
Batch:

DMSO : 100 mg/mL (199.66 mM)
(Met vocht verontreinigd DMSO kan de oplosbaarheid verminderen. Gebruik verse, watervrije DMSO.)

Water : Insoluble

Ethanol : 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.

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

Targets/IC₅₀/Ki	PDGFRβ (Cell-free) RET (Cell-free) 1.5 nM Raf-1 (Cell-free) 2.5 nM murine VEGFR2 (Cell-free) 4.2 nM KIT (Cell-free) 7 nM VEGFR1 (Cell-free) 13 nM B-Raf (V600E) (Cell-free) 19 nM PDGFRβ (Cell-free) 22 nM B-Raf (Cell-free) 28 nM murine VEGFR3 (Cell-free) 46 nM
In vitro	Regorafenib voorkomt sterk VEGFR2-autofosforylering in NIH-3T3/VEGFR2-cellen met een IC50 van 3 nM. In HAoSMC's onderdrukt regorafenib PDGFR-β-autofosforylering na stimulatie met PDGF-BB, met een IC50 van 90 nM. Regorafenib remt ook de FGFR-signalering in MCF-7-borstkankercellen (BC) gestimuleerd met FGF10. Regorafenib remde zeer potent de mutante receptoren KIT^K642E en RET^C634W, met een IC50 van respectievelijk ongeveer 20 nM en 10 nM. Regorafenib remt de proliferatie van VEGF¹⁶⁵-gestimuleerde HUVEC's, met een IC50 van ongeveer 3 nM. Regorafenib voorkomt de proliferatie van FGF2-gestimuleerde HUVEC's en van PDGF-BB-gestimuleerde HAoSMC's met een IC50 van respectievelijk 127 nM en 146 nM. Regorafenib richt zich zowel op tumorcelproliferatie als op tumorvasculatuur door remming van receptoren van tyrosinkinasen (VEGFR, KIT, RET, FGFR en PDGFR) en serine/threoninekinasen (Raf en p38MAPK). Regorafenib onderdrukt de groei van menselijke Hep3B-, PLC/PRF/5- en HepG2-cellen op een concentratie- en tijdsafhankelijke manier.
Kinase Assay	Kinase-assays
Kinase Assay	In vitro assays met recombinant VEGFR2 (murine aa785-aa1367), VEGFR3 (murine aa818-aa1363), PDGFRβ (aa561-aa1106), Raf-1 (aa305-aa648) en BRafV600E (aa409-aa765) kinase domeinen worden uitgevoerd. De initiële in vitro kinase-inhibitieprofilering wordt uitgevoerd bij een vaste 1 μM Regorafenib concentratie. Inhibitoire concentratie van 50% (IC50) waarden worden bepaald uit geselecteerde reagerende kinasen, bijv. VEGFR1 en RET. TIE2 kinase-inhibitie wordt gemeten met een homogene time-resolved fluorescence (HTRF) assay met behulp van een recombinant fusie-eiwit van glutathion-S-transferase, het intracellulaire domein van TIE2 en het peptide biotine-Ahx-EPKDDAYPLYSDFG als substraat.
In vivo	Regorafenib vertoont een potente dosisafhankelijke TGI in verschillende preklinische humane xenograftmodellen bij muizen, met tumorverkleiningen in borst-MDA-MB-231- en nier-786-O-carcinoommodellen. Regorafenib voorkomt niet alleen de groei van syngene primaire 4T1 borsttumoren die orthotoop groeien in het vetkussen, maar onderdrukt ook de vorming van tumormetastasen in de long.
Referenties	[1] https://pubmed.ncbi.nlm.nih.gov/21170960/ [2] https://pubmed.ncbi.nlm.nih.gov/21789125/ [3] https://pubmed.ncbi.nlm.nih.gov/22777740/

Informatie over klinische proeven

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

NCT-nummer	Werving	Aandoeningen	Sponsor/medewerkers	Startdatum	Fasen
NCT03386825	Completed	Colorectal Neoplasms	Bayer	January 31 2018	--
NCT01959269	Completed	Colorectal Neoplasm	Bayer	October 31 2013	--

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