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 IC 50 at 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.

Chiaurinib Selectively Inhibits Colorectal Cancer with KRAS Wild-Type by Modulation of ROS through Activating the p53 Signaling Pathway

“…However, the transcription level of p53 did not change, but the protein level increased signi cantly, indicating that Chiauranib might affect the post-transcriptional regulation of p53. It has been reported that Chiauranib could inhibit the phosphorylation of Aurora B, which participated in regulating p53 phosphorylation 8 . Indeed, our results showed that Chiaurinib could inhibit Aurora B phosphorylation in KRAS wild-type CRC cells, thus inducing p53 increasing ( Fig.…”

“…Chiauranib is a novel oral multi-target small molecule inhibitor of select serine threonine-kinases, including the angiogenesis-related kinases (VEGFR1, VEGFR2, VEGFR3, and c-Kit), the chronic in ammation-related kinase CSF-1R, and the mitosis-related kinase Aurora B, with a variety of potential anti-tumor activities [8][9][10] . Chiauranib reduces hepatocellular carcinoma and gastric cancer cell proliferation by simultaneous inhibiting VEGFR2 and Aurora B 8 . Besides, Chiauranib exerts anti-tumor effect against angiogenesis and mitosis in hematologic tumors, such as acute myeloid leukemia and Non-Hodgkin's lymphomas 9,10 .…”

Drug discovery and computational strategies in the multitarget drugs era

“…The results of the current study concluded that five multi-targeted compounds (S-258282355, S-258012947, S-259417539, S-258002927, and S-259411474) (Figure 30) with high binding energies that range between −8.7 to −10.3 kcal/mol as well as a good ADMET profile against all three targets be taken into consideration, suggesting them as potential hits for drug development against breast cancer after testing through in vitro and in vivo experiments. Zhou et al (2017) used a computer-aided rational drug design approach that led to the synthesis and characterization of CS2164 (N-(2-aminophenyl)-6-[(7methoxy-4-quinolinyl)oxy]-1-naphthalenecarboxamide, Figure 31) and evaluated as a novel multi-kinase inhibitor through the in vitro studies and the molecular docking.…”

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Anlotinib is a multiple RTKI with a broad spectrum of inhibitory action on tumor angiogenesis and growth. CS2164 ( 68 ) is a novel multiple RTKI against tumor angiogenesis . It could suppress the angiogenic RTKs (VEGFR1‐3, PDGFRα, 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 nanomolar range.…”

“…CS2164 (68) is a novel multiple RTKI against tumor angiogenesis. 173 It could suppress the angiogenic RTKs (VEGFR1-3, PDGFR , 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 nanomolar range. It is under clinical assessment for the treatment of cancers.…”