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Regorafenib (BAY-734506) Monohydrate VEGFR Inhibitor

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

Kat.-Nr.S5077

Regorafenib (BAY-734506, Fluoro-sorafenib, Resihance, Stivarga, regorafaenib monohydrate) Monohydrat ist ein neuartiger oraler Multikinase-Inhibitor mit IC50-Werten von 13, 4,2, 46, 22, 7, 1,5, 2,5, 28, 19 nM für VEGFR1, murine VEGFR2, murine VEGFR3, PDGFR-β, Kit (c-Kit), RET (c-RET), RAF-1, B-RAF und B-RAF(V600E).

Regorafenib (BAY-734506) Monohydrate VEGFR Inhibitor Chemical Structure

Chemische Struktur

Molekulargewicht: 500.83

Springe zu

Qualitätskontrolle

Charge: Reinheit: 99.99%

99.99

Verwandte Ziele	EGFR PDGFR FGFR c-Met Src MEK CSF-1R FLT3 HER2 c-Kit
Weitere 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

Zellkultur, Behandlung & Arbeitskonzentration

Zelllinien	Assay-Typ	Inkubationszeit	Aktivitätsbeschreibung	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
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Chemische Informationen, Lagerung & Stabilität

Molekulargewicht	500.83	Formel	C₂₁H₁₅ClF₄N₄O₃.H₂O	Lagerung (Ab dem Eingangsdatum)	3 Jahre-20°CPulver
CAS-Nr.	1019206-88-2	--		Lagerung von Stammlösungen	1 Jahr-80°Cin Lösungsmittel 1 Monat-20°Cin Lösungsmittel
Synonyme	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

Löslichkeit

In vitro
Charge:

DMSO : 100 mg/mL (199.66 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Water : Insoluble

Ethanol : Insoluble

DMSO : 100 mg/mL (199.66 mM)
(Feuchtigkeitskontaminiertes DMSO kann die Löslichkeit verringern. Verwenden Sie frisches, wasserfreies DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molaritätsrechner

Masse	Konzentration	Volumen	Molekulargewicht
=	×	×

Verdünnungsrechner Molekulargewichtsrechner

In vivo Charge:
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-Formulierungsrechner (Klare Lösung)

Schritt 1: Geben Sie die untenstehenden Informationen ein (Empfohlen: Ein zusätzliches Tier zur Berücksichtigung von Verlusten während des Experiments)

Dosierung: mg/kg Durchschnittsgewicht der Tiere: g Dosiervolumen pro Tier:μL Anzahl der Tiere:

Schritt 2: Geben Sie die In-vivo-Formulierung ein (Dies ist nur der Rechner, keine Formulierung. Bitte kontaktieren Sie uns zuerst, wenn es im Abschnitt "Löslichkeit" keine In-vivo-Formulierung gibt.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Berechnungsergebnisse:

Arbeitskonzentration: mg/ml;

Methode zur Herstellung der DMSO-Stammlösung: mg Wirkstoff vorgelöst in μL DMSO ( Konzentration der Stammlösung mg/mL, Bitte kontaktieren Sie uns zuerst, wenn die Konzentration die DMSO-Löslichkeit der Wirkstoffcharge überschreitet. )

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammlösung, dann hinzufügenμL PEG300, mischen und klären, dann hinzufügenμL Tween 80, mischen und klären, dann hinzufügen μL ddH₂O, mischen und klären.

Methode zur Herstellung der In-vivo-Formulierung: Nehmen Sie μL DMSO Stammlösung, dann hinzufügen μL Maisöl, mischen und klären.

Hinweis: 1. Bitte stellen Sie sicher, dass die Flüssigkeit klar ist, bevor Sie das nächste Lösungsmittel hinzufügen.
2. Achten Sie darauf, das/die Lösungsmittel der Reihe nach hinzuzufügen. Sie müssen sicherstellen, dass die bei der vorherigen Zugabe erhaltene Lösung eine klare Lösung ist, bevor Sie mit der Zugabe des nächsten Lösungsmittels fortfahren. Physikalische Methoden wie Vortex, Ultraschall oder ein heißes Wasserbad können zur Unterstützung des Lösens verwendet werden.

Wirkmechanismus

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 verhindert stark die VEGFR2-Autophosphorylierung in NIH-3T3/VEGFR2-Zellen mit einem IC50 von 3 nM. In HAoSMCs unterdrückt Regorafenib die PDGFR-β-Autophosphorylierung nach Stimulation mit PDGF-BB, mit einem IC50 von 90 nM. Regorafenib hemmt auch die FGFR-Signalübertragung in MCF-7-Brustkrebszellen (BC), die mit FGF10 stimuliert wurden. Regorafenib hemmte sehr potent die mutierten Rezeptoren KIT^K642E und RET^C634W mit IC50-Werten von ungefähr 20 nM bzw. 10 nM. Regorafenib hemmt die Proliferation von VEGF¹⁶⁵-stimulierten HUVECs mit einem IC50 von ungefähr 3 nM. Regorafenib verhindert die Proliferation von FGF2-stimulierten HUVECs und von PDGF-BB-stimulierten HAoSMCs mit IC50-Werten von 127 nM bzw. 146 nM. Regorafenib zielt sowohl auf die Tumorzellproliferation als auch auf die Tumorvaskulatur durch Hemmung von Rezeptoren von Tyrosinkinasen (VEGFR, KIT, RET, FGFR und PDGFR) und Serin/Threonin-Kinasen (Raf und p38MAPK) ab. Regorafenib unterdrückt das Wachstum menschlicher Hep3B-, PLC/PRF/5- und HepG2-Zellen konzentrations- und zeitabhängig.
Kinase-Assay	Kinase-Assays
Kinase-Assay	In-vitro-Assays unter Verwendung rekombinanter VEGFR2 (murine aa785-aa1367), VEGFR3 (murine aa818-aa1363), PDGFRβ (aa561-aa1106), Raf-1 (aa305-aa648) und BRafV600E (aa409-aa765) Kinasedomänen werden durchgeführt. Das anfängliche In-vitro-Kinaseinhibitions-Profiling wird bei einer festen Regorafenib-Konzentration von 1 μM durchgeführt. Inhibitorische Konzentration von 50 % (IC50)-Werte werden von ausgewählten reagierenden Kinasen, z. B. VEGFR1 und RET, bestimmt. Die TIE2-Kinasehemmung wird mit einem homogenen zeitaufgelösten Fluoreszenz (HTRF)-Assay unter Verwendung eines rekombinanten Fusionsproteins aus Glutathion-S-Transferase, der intrazellulären Domäne von TIE2 und dem Peptid Biotin-Ahx-EPKDDAYPLYSDFG als Substrat gemessen.
In vivo	Regorafenib zeigt eine potente dosisabhängige TGI in verschiedenen präklinischen humanen Xenograftmodellen bei Mäusen mit Tumorschrumpfungen in Brust-MDA-MB-231- und Nieren-786-O-Karzinommodellen. Regorafenib verhindert nicht nur das Wachstum syngener primärer 4T1-Brusttumoren, die orthotop im Fettpolster wachsen, sondern unterdrückt auch die Bildung von Tumormetastasen in der Lunge.
Literatur	[1] https://pubmed.ncbi.nlm.nih.gov/21170960/ [2] https://pubmed.ncbi.nlm.nih.gov/21789125/ [3] https://pubmed.ncbi.nlm.nih.gov/22777740/

Klinische Studieninformationen

(Daten von https://clinicaltrials.gov, aktualisiert am 2024-05-22)

NCT-Nummer	Rekrutierung	Erkrankungen	Sponsor/Kooperationspartner	Startdatum	Phasen
NCT03386825	Completed	Colorectal Neoplasms	Bayer	January 31 2018	--
NCT01959269	Completed	Colorectal Neoplasm	Bayer	October 31 2013	--

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