Open AccessCS 2164, a novel multi‐target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti‐tumor potency
Author(s) -
Zhou You,
Shan Song,
Li ZhiBin,
Xin LiJun,
Pan DeSi,
Yang QianJiao,
Liu YingPing,
Yue XuPeng,
Liu XiaoRong,
Gao JiZhou,
Zhang JinWen,
Ning ZhiQiang,
Lu XianPing
Publication year - 2017
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13141
Subject(s) - angiogenesis , cancer research , kinase , inflammation , neovascularization , cell growth , mitosis , phosphorylation , pharmacology , biology , microbiology and biotechnology , immunology , biochemistry
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.