Regorafenib

SKU: orb1307437

Description

Regorafenib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor active against key oncogenic and angiogenic receptors including RET, VEGFRs, and PDGFRβ. It exhibits potent antitumor and anti-angiogenic effects, validated in both in vitro assays and in vivo models of colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma.

Research Area

Cardiovascular Research

Key Properties

• CAS Number: 755037-03-7
• MW: 482.8
• Purity: >98%
• Formula: C₂₁H₁₅ClF₄N₄O₃
• SMILES: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(c3)C(F)(F)F)c(F)c2)ccn1
• Target: Kinase
• Solubility: Soluble in DMSO up to 50 mg/ml

Bioactivity

• Target IC50:
  VEGFR2:4.2 nM (cell free)|VEGFR3:46 nM|B-Raf (V600E):19 nM (cell free)|B-Raf:28 nM|Tie2:311 ± 46 nM|RET:1.5 nM (cell free)|VEGFR1:13 nM (cell free)|PDGFRβ:22 nM|CWH22 organoids:3.32 μM|c-Kit:7 nM (cell free)|CLM22 organoids:3.68 μM|Raf-1:2.5 nM (cell free)
• In Vivo:
  METHODS: To test the antitumor activity in vivo, Regorafenib (3-100 mg/kg) was orally administered to NCr nu/nu mice bearing tumors Colo-205 or MDA-MB-231 once daily for nine days. RESULTS: Regorafenib inhibited tumor growth. In the Colo-205 model, Regorafenib at a dose of 10 mg/kg resulted in a TGI of 75% on day 14. In the MDA-MB-231 model, Regorafenib was highly effective at doses as low as 3 mg/kg, resulting in a significant TGI of 81%. METHODS: To assay antitumor activity in vivo, Regorafenib (3-10 mg/kg) was administered orally to NMRI nu/nu mice harboring tumors HT-29 or MDA-MB-231 once daily for twenty-seven days. RESULTS: Regorafenib dose-dependently inhibited HT-29 and MDA-MB-231 tumor growth.
• In Vitro:
  METHODS: Human hepatocellular carcinoma cells Hep3B, PLC/PRF/5 and HepG2 were treated with Regorafenib (0-10 μM) for 72 h. Cell viability was measured by MTT. RESULTS: Regorafenib concentration-dependently decreased the viability of Hep3B cells with an IC50 of about 5 μM. PLC/PRF/5 cells were similarly sensitized to Hep3B cells. However, HepG2 cells were more sensitive, with an IC50 of approximately 1 μM. METHODS: Tumor cells NIH-3T3/VEGFR2, CHO/TIE2, HAoSMC/PDGFR-β and MCF-7/FGFR were treated with Regorafenib (10-3000 nM) for 1 h. The expression levels of the target proteins were detected by Western Blot. RESULTS: Regorafenib inhibited p-VEGFR2, p-TIE2, p-PDGFR-β and p-FGFR.
• Cell Research:
  Each cell line was seeded at 0.3×10^5 cells/2ml of DMEM containing 10% FBS in 35 mm tissue culture dishes. The cells were incubated for 24 h to allow attachment, and then the medium was replaced by fresh culture medium containing Regorafenib at increasing concentrations (1 μM, 2.5 μM, 5 μM, 7.5 μM and 10 μM). In these experimental conditions, the cells were allowed to grow for 72 or 96 h. Time-course experiments on Hep3B cells were performed with 7.5 μM of Regorafenib at short (15, 60, 180 min.), middle (24, 48, 72 and 96 h) or long times (up to seven days). When the cells were treated for long times the drug was replaced with a fresh one. Each experiment included a control with the equivalent concentration of DMSO (solvent control) as the one used for adding Regorafenib. Each experiment was performed in triplicate and repeated 3 times. Subsequent analyses were performed at specific Regorafenib concentrations and incubation times .
• Animal Research:
  Female athymic NCr nu/nu mice, kept in accordance with Federal guidelines, were subcutaneously inoculated with 5×10^6 Colo-205 or MDAMB-231 cells or implanted with 1 mm^3 786-O tumor fragments. When tumors reached a volume of ~100 mm^3, regorafenib or vehicle control was administered orally qd×21 in the 786-O model, and qd×9 in the Colo-205 and MDA-MB231 models, respectively, at doses of 100, 30, 10, and 3 mg/kg. Paclitaxel was administered intravenously at 10 mg/kg in ethanol/Cremophor ELV/saline (12.5%/12.5%/75%) every 2 days×5. Tumor size (volume) was estimated twice weekly (l×w^2)/2, and the percentage of tumor growth inhibition (TGI) was obtained from terminal tumor weights (1-T/C100). Mice were weighed every other day starting from the first day of treatment. The general health status of the mice was monitored daily .

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

BAY 73-4506

Compound Identifiers

PubChem CID

11167602