Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor

Objective: SIM010603 is a structurally novel, oral, multi-targeted receptor tyrosine kinase inhibitor. This study investigated the anti-angiogenic and anti-tumor effects of SIM010603.

Methods: A radiometric protein kinase assay was used for measuring the kinase activity of the 32 protein kinases. Receptor phosphorylation was determined by enzyme-linked immunosorbent assay (ELISA). Cell proliferation was measured by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell chemotaxis was evaluated by modified Boyden chamber assay. Effect of SIM010603 on angiogenesis was examined by mouse cornea angiogenesis assay. Effect of SIM010603 on xenografts was assessed by tumor growth delay. Effects of SIM010603 on tumor microvascular density (MVD), recruitment of pericytes, and pericyte encapsulation of tumor vessels were analyzed by immunofluorescent staining technique.

Results: SIM010603 inhibited stem cell factor receptor (Kit), vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β), glial cell line-derived neurotrophic factor receptor (Rearranged during Transfection; RET), and Fms-like tyrosine kinase-3 (FLT3) with IC(50) values between 5.0 and 68.1 nmol/l. SIM010603 inhibited the phosphorylation of PDGFR-β and VEGFR-2. Moreover, SIM010603 inhibited endothelial cell proliferation, endothelial cells chemotaxis, and corneal angiogenesis. Although SIM010603 exhibited lower activity in regard to proliferation of NCI-H460, MDA-MB-435, and T241-VEGF-A cells (IC(50) > 1 μmol/l), SIM010603 inhibited tumor growth in these xenograft tumor growth models. SIM010603 reduced tumor MVD in T241-VEGF-A tumor xenograft models and decreased positive signals of CD31, NG2 in MDA-MB-435, and LLC-SW-44 xenograft tumor models.

Conclusions: These results support the clinical assessment of SIM010603 as a therapeutic agent for Cancer.