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 IC
50 values in the 4–14nM range, and the ligand-dependent autophosphorylation
of VEGFR2 and PDGFRb with IC
50s 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
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.
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)
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.
Background
Sunitinib, also known as SU11248, is a multi-tyrosine kinase inhibitor widely known to target PDGFR, VEGFR, KIT, and FLT3, and therefore has both antitumor and antiangiogenic activities. Cellular phosphorylation assays show that sunitinib effectively inhibits ligand-dependent phosphorylation of these receptor tyrosine kinases in nanomolar concentrations and can also inhibit ligand-dependent cellular proliferation. Sunitinib displays greater than 10-fold selectively for PDGFRB and VEGFR over numerous other kinases, including EGFR, Cdk2, Met, IGF -1R, Abl, and src. Inhibition of CSF-1 and RET by sunitinib has also been observed.This product has applications to SARS-CoV-2 research into the mechanisms of the Novel Coronavirus, which has caused the COVID-19 pandemic.
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.
