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835621-07-3

835621-07-3 structure
835621-07-3 structure
  • Name: Regorafenib (Hydrochloride)
  • Chemical Name: 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrochloride
  • CAS Number: 835621-07-3
  • Molecular Formula: C21H16Cl2F4N4O3
  • Molecular Weight: 519.276
  • Catalog: Signaling Pathways Autophagy Autophagy
  • Create Date: 2018-05-16 08:00:00
  • Modify Date: 2024-01-02 13:57:50
  • Regorafenib Hydrochloride is a multi-target inhibitor for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1 with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM, respectively.

Name 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrochloride
Synonyms CS-0725
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl-2-pyridinecarboxamide hydrochloride (1:1)
2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl-, hydrochloride (1:1)
Regorafenib Hydrochloride
Regorafenib (Hydrochloride)
Description Regorafenib Hydrochloride is a multi-target inhibitor for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1 with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM, respectively.
Related Catalog
Target

VEGFR1:13 nM (IC50)

VEGFR2:4.2 nM (IC50)

VEGFR3:46 nM (IC50)

PDGFRβ:22 nM (IC50)

Braf:28 nM (IC50)

BRafV600E:19 nM (IC50)

Raf-1:2.5 nM (IC50)

In Vitro Regorafenib potently inhibits VEGFR2 autophosphorylation in NIH-3T3/VEGFR2 cells with an IC50 of 3 nM. In HAoSMCs, regorafenib inhibits PDGFR-β autophosphorylation after stimulation with PDGF-BB, with an IC50 of 90 nM. Regorafenib inhibits the proliferation of VEGF165-stimulated HUVECs, with an IC50 of 3 nM[1]. Regorafenib causes a concentration-dependent decrease in Hep3B cell growth, having an IC50 of 5 μM. Regorafenib subsequently increases the levels of phospho-c-Jun, a JNK target, but not total c-Jun in Hep3B cells[3].
In Vivo Regorafenib effectively inhibits growth of the Colo-205 xenografts in the dose range of 10-100 mg/kg reaching a TGI of 75% at day 14 at the 10 mg/kg dose. In the MDA-MB-231 model, regorafenib is highly efficacious at a dose as low as 3 mg/kg, resulting in a significant TGI of 81%, which increases to 93% at doses of 10 and 30 mg/kg, where tumor stasis is reached[1].
Kinase Assay Initial in vitro kinase inhibition profiling is performed at Millipore Corporation at a fixed 1 μM compound concentration under Millipore standard conditions [10 μM adenosine-5′-triphosphate (ATP) 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.
Cell Assay 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°C. 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 hr. Cell proliferation is quantified using CellTitre-GloTM.
Animal Admin Female athymic NCr nu/nu mice, kept in accordance with Federal guidelines, are subcutaneously inoculated with 5×106 Colo-205 or MDA-MB-231 cells or implanted with 1 mm3 786-O tumor fragments. When tumors reach a volume of 100 mm3, regorafenib or vehicle control is administered orally qd×21 in the 786-O model, and qd×9 in the Colo-205 and MDA-MB-231 models, respectively, at doses of 100, 30, 10, and 3 mg/kg. Paclitaxel is administered intravenously at 10 mg/kg in ethanol/Cremophor EL®/saline (12.5%/12.5%/75%) every 2 days×5. Tumor size (volume) is estimated twice weekly (l×w2)/2, and the percentage of tumor growth inhibition (TGI) is obtained from terminal tumor weights (1-T/C×100). Mice are weighed every other day starting from the first day of treatment. The general health status of the mice is monitored daily.
References

[1]. Wilhelm SM, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer, 2011, 129(1), 245-255.

[2]. Heng DY, et al. Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions. Ther Adv Med Oncol, 2010, 2(1), 39-49.

[3]. Carr BI, et al. Fluoro-Sorafenib (Regorafenib) effects on hepatoma cells: growth inhibition, quiescence, and recovery. J Cell Physiol, 2013, 228(2), 292-297.

Molecular Formula C21H16Cl2F4N4O3
Molecular Weight 519.276
Exact Mass 518.053589
PSA 95.84000
LogP 6.96830
Storage condition 2-8℃

~79%

835621-07-3 structure

835621-07-3

Literature: BAYER PHARMACEUTICALS CORPORATION Patent: WO2008/89389 A2, 2008 ; Location in patent: Page/Page column 15 ;

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835621-07-3 structure

835621-07-3

Literature: WO2011/130728 A1, ; WO 2011/130728 A1

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835621-07-3 structure

835621-07-3

Literature: WO2011/130728 A1, ; WO 2011/130728 A1

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835621-07-3 structure

835621-07-3

Literature: WO2011/130728 A1, ; WO 2011/130728 A1