Sunitinib

Sunitinib (SU 11248) is an orally active multi-target receptor tyrosine kinase inhibitor with IC₅₀ values of 80 nM and 2 nM for vascular endothelial growth factor receptor (VEGFR2) and platelet-derived growth factor receptor (PDGFRβ), respectively^[1]. Sunitinib is an ATP-competitive inhibitor that effectively inhibits the phosphorylation of Ire1α by inhibiting autophosphorylation and subsequent RNase activation^[2]. Sunitinib is commonly used to treat advanced renal cell carcinoma and gastrointestinal stromal cancer, as well as non-small cell lung cancer^[3].

In vitro, treatment of renal cancer cell 786-O with Sunitinib (2, 5 μM) induced changes in the intracellular phosphorylated proteome, with 180 phosphopeptides showing >1.5-fold changes, 86 phosphopeptides downregulated, and 94 phosphopeptides upregulated^[4]. Sunitinib (0-5μM) treatment of medulloblastoma VC312 cells for 24h or 48h increased the levels of cleaved caspase-3 and PARP in a dose-dependent manner, induced cell apoptosis, and inhibited STAT3 and AKT activity^[5].

In vivo, oral treatment of mice inoculated with 4T1-luc and RENCA-luc tumor cells with Sunitinib (30, 60, 120mg/kg) failed to inhibit the growth of 4T1 tumors after mouse lung implantation, but significantly inhibited the growth of RENCA tumors^[6]. Sunitinib (1mg/kg) treatment of diabetic rats for 4 weeks significantly reduced ovarian stromal degeneration, stromal fibrosis, follicular degeneration, and immune expression of NF-kappaB^[7].

References:
[1] Sun L, Liang C, Shirazian S, et al. Discovery of 5-[5-fluoro-2-oxo-1, 2-dihydroindol-(3 Z)-ylidenemethyl]-2, 4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase[J]. Journal of medicinal chemistry, 2003, 46(7): 1116-1119.
[2] Ali M M U, Bagratuni T, Davenport E L, et al. Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response[J]. The EMBO journal, 2011, 30(5): 894-905.
[3] Gridelli C, Maione P, Del Gaizo F, et al. Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer[J]. The oncologist, 2007, 12(2): 191-200.
[4] Van Der Mijn J C, Broxterman H J, Knol J C, et al. Sunitinib activates Axl signaling in renal cell cancer[J]. International journal of cancer, 2016, 138(12): 3002-3010.
[5] Yang F, Jove V, Xin H, et al. Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways[J]. Molecular Cancer Research, 2010, 8(1): 35-45.
[6] Welti J C, Powles T, Foo S, et al. Contrasting effects of sunitinib within in vivo models of metastasis[J]. Angiogenesis, 2012, 15: 623-641.
[7] Erbas O, Pala H G, Pala E E, et al. Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study[J]. Gynecological Endocrinology, 2015, 31(5): 388-391.

舒尼替尼Sunitinib（SU 11248）是一种具口服活性的多靶点受体酪氨酸激酶抑制剂，对血管内皮生长因子受体（VEGFR2）和血小板衍生生长因子受体（PDGFRβ）的IC₅₀分别为80nM和2nM^[1]。Sunitinib是一种ATP竞争性抑制剂，通过抑制自身磷酸化和随后的RNase激活，有效抑制Ire1α的磷酸化^[2]。Sunitinib通常用于治疗晚期肾细胞癌和胃肠道间质癌，以及非小细胞肺癌等^[3]。

在体外，Sunitinib（2、5μM）处理肾癌细胞786-O，诱导了胞内磷酸化蛋白质组变化，180 种磷酸肽显示出>1.5倍的变化，86个磷酸肽下调，94个磷酸肽上调^[4]。Sunitinib（0-5μM）处理髓母细胞瘤 VC312 细胞24h或48h，以剂量依赖性方式增加了裂解的caspase-3和PARP水平，诱导了细胞凋亡，抑制了STAT3和AKT活性^[5]。

在体内，Sunitinib（30、60、120mg/kg）通过口服治疗接种4T1-luc和RENCA-luc肿瘤细胞的小鼠，无法抑制4T1肿瘤在小鼠肺部植入后的生长，但可以显著抑制RENCA肿瘤的生长^[6]。Sunitinib（1mg/kg）治疗糖尿病大鼠4周，显著降低了卵巢的间质变性、间质纤维化、卵泡变性以及NF-kappaB的免疫表达^[7]。