title: CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.
abstract: 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, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50at a single-digit nanomolar range. Consequently, CS2164 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. CS2164 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, CS2164 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 CS2164 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 CS2164 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 CS2164 as a therapeutic agent in the treatment of cancer.
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Song
authors.initials: S
authors.lastname: Shan
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Li
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Xin
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: De-Si
authors.initials: DS
authors.lastname: Pan
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Qian-Jiao
authors.initials: QJ
authors.lastname: Yang
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Ying-Ping
authors.initials: YP
authors.lastname: Liu
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Xu-Peng
authors.initials: XP
authors.lastname: Yue
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Liu
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Ji-Zhou
authors.initials: JZ
authors.lastname: Gao
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Jin-Wen
authors.initials: JW
authors.lastname: Zhang
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Ning
authors.affiliation: Shenzhen Chipscreen Biosciences Ltd, Shenzhen, Guangdong, China.
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Lu
mesh_terms: D016475:3T3 Cells; D000230:Adenocarcinoma / Q000188:drug therapy*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D062105:Molecular Docking Simulation; D009281:Naphthalenes; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010655:Phenylenediamines / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D006657:Histones; D009281:Naphthalenes; D010655:Phenylenediamines; D011804:Quinolines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040262:Receptors, Vascular Endothelial Growth Factor; D064107:Aurora Kinase B; C000705608:chiauranib
keywords: Angiogenesis; anti-tumor activity; chronic inflammation; kinase inhibitor; mitosis