Usage
BAY 73-4506 (Regorafenib,755037-03-7) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf.
Usage
Regorafenib (BAY 73-4506,755037-03-7) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively
Usage
It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.
Uses
Regorafenib (BAY 73-4506,755037-03-7) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively
Uses
BAY 73-4506 (Regorafenib) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf.
Uses
It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.
Definition
ChEBI: A pyridinecarboxamide obtained by condensation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxylic acid with methylamine. Used for for the treatment of metastatic colorectal cancer in patients who have previ
usly received chemotherapy, anti-EGFR or anti-VEGF therapy.
Description
In September 2012, theUSFDAapproved regorafenib(755037-03-7) for the treatment of patients with metastatic colorectal cancer (CRC), especially those for whom standard therapies have failed, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, ananti-EGFRtherapy. Regorafenib is a multikinase inhibitor with potent inhibitory activity versus VEGFRs and PDFRs. Both of these classes of receptors are expressed on tumor cells and affect proliferation and angiogenesis. Regorafenib inhibited growth in murine xenograft models for colon, breast, renal, lung, melanoma, pancreatic, and ovarian tumors when dosed at 10–30 mg/kg. Regorafenib is a fluorinated analog of sorafenib, a multikinase inhibitor co-marketed by Bayer and Onyx for the treatment of kidney and liver cancer. The synthesis of regorafenib is accomplished in two steps from commercially available starting materials. 4-Aminophenol is coupled to 4-chloro-N-methyl- 2-pyridinecarboxamide to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. Subsequent treatment with 4-chloro-3-(trifluoromethyl)phenyl isocycanate affords the urea, regorafenib.
Originator
Bayer (Germany)
Characteristics
Class: receptor tyrosine kinase
Treatment: colorectal cancer, GIST, HCC
Elimination half-life = 26-28 h
Protein binding = 99.5%
Clinical Use
Treatment of colorectal cancer and gastrointestinal
stromal tumours
Treatment of hepatocellular carcinoma
Drug interactions
Potentially hazardous interactions with other drugs
Analgesics: avoid with mefenamic acid.
Antibacterials: concentration reduced by rifampicin
- avoid.
Anticoagulants: increased risk of bleeding with
warfarin.
Antifungals: concentration increased by ketoconazole
- avoid.
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis).
Metabolism
Regorafenib(755037-03-7) is metabolised by CYP3A4 and UGT1A9.
The main circulating metabolites of regorafenib measured
at steady-state in human plasma are M-2 (N-oxide) and
M-5 (N-oxide and N-desmethyl), both of them having
similar in vitro pharmacological activity and steady-state
concentrations as regorafenib. M-2 and M-5 are highly
protein bound (99.8% and 99.95%, respectively).
Approximately 90% of the radioactive dose was recovered
within 12 days after administration, with about 71% of
the dose excreted in faeces (47% as parent compound,
24% as metabolites), and about 19% of the dose
excreted in urine as glucuronides. Urinary excretion of
glucuronides decreased below 10% under steady-state
conditions. Parent compound found in faeces could be
derived from intestinal degradation of glucuronides
or reduction of metabolite M-2 (N-oxide), as well as
unabsorbed regorafenib.
storage
Desiccate at -20°C
References
[1]. wilhelm sm, dumas j, adnane l, 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]. schmieder r, hoffmann j, becker m, et al. regorafenib (bay 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. int j cancer, 2014, 135(6): 1487-1496.
