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Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti‐cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi‐kinase inhibitor,  CS 2164.  CS 2164 inhibited the angiogenesis‐related kinases ( VEGFR 2,  VEGFR 1,  VEGFR 3,  PDGFR α and c‐Kit), mitosis‐related kinase Aurora B and chronic inflammation‐related kinase  CSF ‐1R in a high potency manner with the  IC  50  at a single‐digit nanomolar range. Consequently,  CS 2164 displayed anti‐angiogenic activities through suppression of  VEGFR / PDGFR  phosphorylation, inhibition of ligand‐dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues.  CS 2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B‐mediated H3 phosphorylation. Furthermore,  CS 2164 demonstrated the inhibitory effect on  CSF ‐1R phosphorylation that led to the suppression of ligand‐stimulated monocyte‐to‐macrophage differentiation and reduced  CSF ‐1R +  cells in tumor tissues. The  in vivo  animal efficacy studies revealed that  CS 2164 induced remarkable regression or complete inhibition of tumor growth at well‐tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that  CS 2164 is a highly selective multi‐kinase inhibitor with potent anti‐tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of  CS 2164 as a therapeutic agent in the treatment of cancer.

CS 2164, a novel multi‐target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti‐tumor potency