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Regorafenib (BAY 73-4506)

Names

[ CAS No. ]:
755037-03-7

[ Name ]:
Regorafenib (BAY 73-4506)

[Synonym ]:
BAY734506
2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino] carbonyl]amino]-3-fluorophenoxy]-N-methyl-
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
Regorafenib
4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide
Stivarga
BAY73-4506
4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl-2-pyridinecarboxamide
2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]-3-fluorophenoxy]-N-methyl-
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
BAY 73-4506

Biological Activity

[Description]:

Regorafenib (BAY 73-4506) is a multi-targeted receptor tyrosine kinase inhibitor with IC50s of 13/4.2/46, 22, 7, 1.5 and 2.5 nM for VEGFR1/2/3, PDGFRβ, Kit, RET and Raf-1, respectively.

[Related Catalog]:

Signaling Pathways >> Autophagy >> Autophagy
Signaling Pathways >> Protein Tyrosine Kinase/RTK >> PDGFR
Signaling Pathways >> MAPK/ERK Pathway >> Raf
Signaling Pathways >> Protein Tyrosine Kinase/RTK >> VEGFR
Research Areas >> Cancer

[Target]

VEGFR1:13 nM (IC50)

VEGFR2:4.2 nM (IC50)

VEGFR3:46 nM (IC50)

PDGFRβ:22 nM (IC50)

Raf-1:2.5 nM (IC50)

Braf:28 nM (IC50)

BRafV600E:19 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.

[4]. Wagner J, et al. Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms. J Exp Clin Cancer Res. 2018 Jan 22;37(1):11.

[5]. Matsuoka K, et al. Effective Sequential Combined Chemotherapy with Trifluridine/Tipiracil and Regorafenib in Human Colorectal Cancer Cells. Int J Mol Sci. 2018 Sep 25;19(10). pii: E2915.


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Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Boiling Point ]:
513.4±50.0 °C at 760 mmHg

[ Melting Point ]:
206.0 to 210.0 °C

[ Molecular Formula ]:
C21H15ClF4N4O3

[ Molecular Weight ]:
482.815

[ Flash Point ]:
264.3±30.1 °C

[ Exact Mass ]:
482.076874

[ PSA ]:
92.35000

[ LogP ]:
5.26

[ Vapour Pressure ]:
0.0±1.3 mmHg at 25°C

[ Index of Refraction ]:
1.616

Safety Information

[ Hazard Codes ]:
Xi

[ HS Code ]:
29242990

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds