Sunitinib also potently inhibits Kit and FLT-3. Sunitinib is a potent ATP-competitive inhibitor of VEGFR2 (Flk1) and PDGFRβ with Ki of 9 nM and 8 nM, respectively, displaying >10-fold higher selectivity for VEGFR2 and PDGFR than FGFR-1, EGFR, Cdk2, Met, IGFR-1, Abl, and src. In serum-starved NIH-3T3 cells expressing VEGFR2 or PDGFRβ, Sunitinib inhibits VEGF-dependent VEGFR2 phosphorylation and PDGF-dependent PDGFRβ phosphorylation with IC50 of 10 nM and 10 nM, respectively. Sunitinib inhibits VEGF-induced proliferation of serum-starved HUVECs with IC50 of 40 nM, and inhibits PDGF-induced proliferation of NIH-3T3 cells overexpressing PDGFRβ or PDGFRα with IC50 of 39 nM and 69 nM, respectively. Sunitinib inhibits phosphorylation of wild-type FLT3, FLT3-ITD, and FLT3-Asp835 with IC50 of 250 nM, 50 nM, and 30 nM, respectively. Sunitinib inhibits the proliferation of MV4;11 and OC1-AML5 cells with IC50 of 8 nM and 14 nM, respectively, and induces apoptosis in a dose-dependent manner.
|Cell lines||RS4;11, MV4;11, and OC1-AML5|
|Preparation method||Cells are starved overnight in medium containing 0.1% FBS prior to addition of Sunitinib and FL (50 ng/mL; FLT3-WT cells only). Proliferation is measured after 48 hours of culture using the Alamar Blue assay or trypan blue cell viability assays. Apoptosis is measured 24 hours after Sunitinib addition by Western blotting to detect cleavage of poly (ADP-ribose) polymerase (PARP) or levels of caspase-3.|
|Concentrations||Dissolved in DMSO, final concentrations ~10 μM|
|Incubation time||24 and 48 hours|
|Animal models||Female nu/nu mice implanted s.c. with HT-29, A431, Colo205, H-460, SF763T, C6, A375, or MDA-MB-435, and male nu/nu mice bearing luciferase-expressing PC-3M tumors|
|Formulation||Formulated as a carboxymethyl cellulose suspension or as a citrate buffered (pH 3.5) solution|
|Administration||Orally once daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||25 mg/mL warmed in DMSO|
Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux.
Giuliano S, et al. Autophagy. 2015;11(10):1891-904. PMID: 26312386.
Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.
Shibasaki N, et al. PLoS One. 2015 Jun 26;10(6):e0130980. PMID: 26114873.
|Related VEGFR/PDGFR Products|
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BAW2881 (NVP-BAW2881) is a potent and selective VEGFR2 inhibitor with activity to inhibit chronic and acute skin inflammation.
SU 1498 is a selective inhibitor of the receptor tyrosine kinase VEGF receptor 2 (VEGFR2, aka FLK1; IC50 = 700 nM).
Avitinib maleate is a pyrrolopyrimidine-based irreversible epidermal growth factor receptor (EGFR) inhibitor with an IC50 of 7.68 nM.
Fruquintinib (HMPL-013) is a highly potent and selective VEGFR 1/2/3 inhibitor with IC50s of 33, 0.35, and 35 nM, respectively.
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