Regorafenib (BAY-734506) Monohydrate

製品コードS5077 バッチS507702

化学情報

	Synonyms	Fluoro-sorafenib, Resihance, Stivarga, regorafaenib monohydrate	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₁H₁₅ClF₄N₄O₃.H₂O
	分子量	500.83	CAS No.	1019206-88-2
Solubility (25°C)*	体外	DMSO	100 mg/mL (199.66 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	Regorafenib (BAY-734506, Fluoro-sorafenib, Resihance, Stivarga) Monohydrate is a novel oral multikinase inhibitor with IC50 values of 13, 4.2, 46, 22, 7, 1.5, 2.5, 28, 19 nM for VEGFR1, murine VEGFR2, murine VEGFR3, PDGFR-β, Kit (c-Kit), RET (c-RET), RAF-1, B-RAF and B-RAF(V600E) respectively.
in vitro	Regorafenib strongly prevents VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with IC50 of 3 nM. In HAoSMCs, regorafenib suppress PDGFR-β autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib also inhibits FGFR signaling in MCF-7 breast cancer (BC) cells stimulated with FGF10. Regorafenib very potently inhibited the mutant receptors KIT^K642E and RET^C634W, with IC50 of approximately 20 nM and 10 nM, respectively. Regorafenib inhibits the proliferation of VEGF¹⁶⁵-stimulated HUVECs, with an IC50 of approximately 3 nM. Regorafenib prevents the proliferation of FGF2-stimulated HUVECs and of PDGF-BB-stimulated HAoSMCs with IC50 of 127 nM and 146 nM, respectively. ^[1] Regorafenib targets both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (Raf and p38MAPK). ^[2] Regorafenib suppresses growth of human Hep3B, PLC/PRF/5 and HepG2 cells in a concentration- and time-dependent manner. ^[3]
in vivo	Regorafenib reveals potent dose-dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages in breast MDA-MB-231 and renal 786-O carcinoma models. Regorafenib prevents not only the growth of syngeneic primary 4T1 breast tumors growing orthotopically in the fat pad, but also suppresses the formation of tumor metastasis in the lung. ^[1]

プロトコル(参考用のみ)

キナーゼアッセイ	Kinase assays
キナーゼアッセイ	In vitro assays using recombinant VEGFR2 (murine aa785-aa1367), VEGFR3 (murine aa818-aa1363), PDGFRβ (aa561-aa1106), Raf-1 (aa305-aa648) and BRafV600E (aa409-aa765) kinase domains are performed. Initial in vitro kinase inhibition profiling is performed at a fixed 1 μM Regorafenib concentration. Inhibitory concentration of 50% (IC50) values are determined from selected responding kinases, e.g., VEGFR1 and RET. TIE2 kinase inhibition is measured with a homogeneous time-resolved fluorescence (HTRF) assay using a recombinant fusion protein of glutathione-S-transferase, the intracellular domain of TIE2 and the peptide biotin-Ahx-EPKDDAYPLYSDFG as substrate.
細胞アッセイ	細胞株	GIST 882 and TT cells
	濃度	5 nM-10 μM
	反応時間	96 h
	実験の流れ	For proliferation assays, GIST 882 and TT cells are grown in RPMI medium containing L-glutamine, and MDA-MB-231, HepG2 and A375 cells in DMEM always containing 10% hiFBS. Cells are trypsinized, plated at 5×10⁴ cells/well in 96-well plates in complete media containing 10% FBS and grown overnight at 37℃. The next day, vehicle or Regorafenib serially diluted in complete growth media to between 10 μM and 5 nM final concentrations, and 0.2% DMSO, is added and incubation is continued for 96 hours. Cell proliferation is quantified.
動物実験	動物モデル	Female athymic NCr nu/nu mice with Colo-205, MDA-MB-231 or 786-O
	投薬量	3 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg
	投与方法	orally

参考

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Effect of Intraperitoneal Chemotherapy with Regorafenib on IL-6 and TNF-α Levels and Peritoneal Cytology: Experimental Study in Rats with Colorectal Peritoneal Carcinomatosis [ J Clin Med, 2023, 12(23)7267]	PubMed: 38068319
Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation [ J Hematol Oncol, 2022, 15(1):109]	PubMed: 35978321
Studies on Biological and Molecular Effects of Small-Molecule Kinase Inhibitors on Human Glioblastoma Cells and Organotypic Brain Slices [ Life (Basel), 2022, 12(8)1258]	PubMed: 36013437
Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients [ Anticancer Drugs, 2022, 10.1097/CAD.0000000000001344]	PubMed: 36066384
Regorafenib and reactive metabolite of sunitinib activate inflammasomes: Implications for multi tyrosine kinase inhibitor-Iiduced immune related adverse events [ Pharmazie, 2022, 77(2):54-58]	PubMed: 35209964
Impact of a Desmoplastic Tumor Microenvironment for Colon Cancer Drug Sensitivity: A Study with 3D Chimeric Tumor Spheroids [ ACS Appl Mater Interfaces, 2021, 13(41):48478-48491]	PubMed: 34633791
Recapitulating cholangiopathy-associated necroptotic cell death in vitro using human cholangiocyte organoids [ Cell Mol Gastroenterol Hepatol, 2021, S2352-345X(21)00223-X]	PubMed: 34700031
Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding [ Cancer Immunol Immunother, 2021, 70(1):203-213]	PubMed: 32683508
Autophagy-Related Chemoprotection against Sorafenib in Human Hepatocarcinoma: Role of FOXO3 Upregulation and Modulation by Regorafenib [ Int J Mol Sci, 2021, 22(21)11770]	PubMed: 34769197
Therapeutic Potential of Regorafenib-A Multikinase Inhibitor in Pulmonary Hypertension [ Int J Mol Sci, 2021, 22(3)1502]	PubMed: 33540939

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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