Description
In January 2012, the US FDA approved axitinib (319460-85-0) (also referred to as
AG-013736) for the treatment of advanced renal cell carcinoma (RCC)
for patients who have not responded to prior therapy.
Axitinib is a pan VEGF inhibitor and functions by binding to
the intracellular tyrosine kinase catalytic domain of VEGF leading to blockade of signaling through this angiogenic pathway. Axitinib is50–400 times more potent for VEGF (enzyme Ki and cellular IC50s for VEGF 1, 2, and 3 are ～0.1 nM) than first-generation inhibitors like sorafenib and sunitinib. Axitinib also inhibits c-Kit and PDGFR(α/β) with enzyme Ki's of
～2 nM and was selective when tested against a broad panel of other protein
kinases. Axitinib was discovered by a structure-based drug design approach
and binds to the kinase domain of VEGF in a DFG-out conformation.
Axitinib blocks VEGF-2 phosphorylation up to 7 h postdose in vivo and
inhibits endothelial cell proliferation in xenograft tumors implanted in
mice. Synthetic routes to axitinib employing a Migita coupling to form
the diaryl sulfide and a Heck reaction to install the 2-styrylpyridine moiety have been reported.
Chemical Properties
Off-White Solid
Originator
Pfizer (United States)
Characteristics
Class: receptor tyrosine kinase
Treatment: RCC
Oral bioavailability = 58%
Elimination half-life = 2.5–6.1 h
Protein binding = 99%
Uses
A tyrosine kinase inhibitor; used in cancer therapy.
Uses
Axitinib (AG-013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively.
Uses
Axitinib is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively.
Uses
Axitinib is a tyrosine kinase inhibitor. Axitinib is used in cancer therapy.
Definition
ChEBI: An indazole substituted at position 3 by a 2-(pyridin-2-yl)vinyl group and at position 6 by a 2-(N-methylaminocarboxy)phenylsulfanyl group. Used for the treatment of advanced renal cell carcinoma after failure of a first line systemic tr
atment.
Biochem/physiol Actions
Axitinib (AG-013736) is an orally available, potent (picomolar) and selective tyrosine kinase inhibitor that blocks VEGF receptors 1, 2 and 3. The drug blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase.
Clinical Use
Sold under the brand name Inlyta® by Pfizer, Inc., axitinib was approved by the FDA in January 2012
for the treatment of advanced renal cell carcinoma (RCC), specifically after the failure of other systemic treatments. Axitinib slows cancer cell proliferation by inhibition of the vascular endothelial growth
factor (VEGF)/VEGF receptor tyrosine (RTK) signaling pathway. In particular, axitinib is a potent
inhibitor of VEGF/RTK 1-3, which selectively slows angiogenesis, vascular permeability, and blood
flow in solid tumors.
Side effects
The side effects that you should report to your doctor include:
allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue;
high blood pressure;
seizures;
signs and symptoms of bleeding such as bloody or black, tarry stools; red or dark-brown urine; spitting up blood or brown material that looks like coffee grounds; red spots on the skin; unusual bruising or bleeding from the eye, gums, or nose;
signs and symptoms of a blood clot such as breathing problems; changes in vision; chest pain; severe, sudden headache; pain, swelling, warmth in the leg; trouble speaking; sudden numbness or weakness of the face, arm, or leg;
stomach pain.
The side effects that usually do not require medical attention include constipation cough, diarrhea, loss of appetite, nausea, and vomiting.
Synthesis
Numerous patents and papers have been disclosed on the synthesis of
axitinib, a recently published manuscript details the development of the manufacturing route, and
this route is depicted in the scheme. The synthesis began with Migita coupling of commercial iodide 17
with thiophenol 18. Interestingly, this transformation?ˉs efficiency relied upon attention to the number of
equivalents of base and an inert atmosphere in the reaction vessel, conditions which minimized catalyst
poisoning during the reaction. Without isolation, indazole 19 was iodinated to afford diarylthioether 20
in 85-90% yield over the two steps. Protection of the indazole within 20 as its acetamide preceeded a
Heck reaction with 2-vinylpyridine, and then subsequent removal of the indazole protection followed by
a series of recrystallizations yielded axitinib (IV) in a combined 62% yield over the final 4 steps.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk
of agranulocytosis); avoid with pimozide.
Concomitant use with strong CYP3A4/5 inhibitors:
avoid; however, if concomitant use cannot be avoided
then reduce the dose of axitinib by approximately
half; subsequent doses can be increased or decreased
based on individual safety and tolerability; if
CYP3A4/5 inhibitor is discontinued, then increase
the axitinib dose used prior to initiation of the
strong inhibitor after 3-5 half-lives of the inhibitor
(strong CYP3A4/5 inhibitors include ketoconazole,
itraconazole, clarithromycin, atazanavir, indinavir,
ritonavir, saquinavir, and voriconazole).
Metabolism
Axitinib is metabolised primarily in the liver by
CYP3A4/5 and to a lesser extent by CYP1A2,
CYP2C19, and UGT1A1.
Most of the drug is excreted via the faeces and urine as
metabolites.
References
1) Hu-Lowe?et al.?(2008),?Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1,2,3; Cancer Res.,?14?7272
2) Ma and Waxman (2008),?Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib; Mol. Cancer Ther.,?7?79
3) Pemovska?et al.?(2015),?Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation; Nature,?519?102
4) Rixe?et al.?(2007),?Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer; a phase II study; Lancet Oncol.,?8?975
5) Yuan?et al.?(2014),?Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation;?Biomed.Pharmacother.?68?751
6) Zhang?et al.?(2014),?Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity;?Anticancer Drugs?25?204
