Sunitinib Chemical Properties

Melting point:

189-191°C

Boiling point:

572.1±50.0 °C(Predicted)

Density 

1.2

Flash point:

299.8℃

storage temp. 

2-8°C

solubility 

Chloroform (Slightly), Methanol (Slightly)

pka

8.5(at 25℃)

form 

Solid

color 

Yellow to Dark Orange

CAS DataBase Reference

557795-19-4(CAS DataBase Reference)

Safety Information

Safety Statements 

24/25

HS Code 

29337900

Hazardous Substances Data

557795-19-4(Hazardous Substances Data)

Sunitinib Usage And Synthesis

Binding Mode

Sunitinib binds the DFG-out conformation of VEGFR2 at the front cleft and gate area (type II). It occupies the ATP-binding site, forming three hydrogen bonds: (1) between the oxindole NH and the amide carbonyl of Glu-917 of the hinge, (2) the oxindole carbonyl and the amide NH of Cys919, and (3) the pyrrole NH and the amide carbonyl of Cys919. Several hydrophobic interactions with VEGFR also contribute to the potency.

Description

Sunitinib is an inhibitor of multiple receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, including platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), and stem cell factor receptor (KIT). It was launched as an oral treatment for gastrointestinal stromal tumors (GIST) and advanced renal-cell carcinoma (RCC). In vitro, sunitib inhibits VEGFR2, PDGFRα, PDGFRβ, KIT, and FLT3 receptors with IC₅₀ values in the 4–14nM range, and the ligand-dependent autophosphorylation of VEGFR2 and PDGFRb with IC₅₀s of approximately 10 nM. In addition, it inhibits the growth of tumor cells expressing dysregulated target RTKs in vitro and inhibits PDGFRb- and VEGFR2-dependent tumor angiogenesis in vivo. Sunitinib exhibits broad and potent antitumor activity, causing regression in murine models of human epidermal (A431), colon (Colo205 and HT-29), lung (NCI-H226 and H460), breast (MDA-MB-435), prostate (PC3-3M-luc), and renal (786-O) cancers, and suppressing or delaying the growth of many others, including the C6 rat and SF763 T human glioma xenografts and B16 melanoma lung cancer.

Chemical Properties

Yellow Solid

Originator

Sugen (US)

Uses

Sunitinib Malate (Sutent, SU11248) is a multi-targeted RTK inhibitor targeting VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM, and also inhibits c-Kit.

Uses

Labelled Sunitinib (S820000), a multi-kinase inhibitor targeting several receptor tyrosine kinases (RTK).

Definition

ChEBI: Sunitinib is a member of pyrroles and a monocarboxylic acid amide. It has a role as an angiogenesis inhibitor, an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, a vascular endothelial growth factor receptor antagonist, an immunomodulator and a neuroprotective agent. It is functionally related to a 3-methyleneoxindole.

brand name

(Pfizer).

Characteristics

Class: receptor tyrosine kinase
Treatment: RCC, GIST
Elimination half-life = 70 h
Protein binding = 95%

Clinical Use

Tyrosine kinase inhibitor:
Treatment of metastatic renal cell carcinoma (MRCC), gastrointestinal stromal tumours (GIST) and pancreatic neuroendocrine tumours (pNET)

target

VEGFR-1

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Antivirals: avoid concomitant use with boceprevir.
Avoid concomitant use with other inhibitors or inducers of CYP3A4. Dose alterations may be required.

Metabolism

Metabolised mainly via the cytochrome P450 isoenzyme CYP3A4 to its primary active metabolite, which itself is then further metabolised via CYP3A4.
Elimination is primarily via faeces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in faeces and 16% by the renal route.

References

[1]hui ep1, lui vw, wong cs, ma bb, lau cp, cheung cs, ho k, cheng sh, ng mh, chan at. preclinical evaluation of sunitinib as single agent or in combination with chemotherapy in nasopharyngeal carcinoma. invest new drugs. 2011 dec;29(6):1123-31.

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