Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents

Aurora
and polo-like kinases control the G2/M phase in cell mitosis,
which are both considered as crucial targets for cancer cell proliferations.
Here, naphthalene-based Aurora/PLK coinhibitors as leading compounds
were designed through in silico approach, and a total of 36 derivatives
were synthesized. One candidate (AAPK-25) was selected under in vitro
cell based high throughput screening with an IC50 value
= 0.4 μM to human colon cancer cell HCT-116. A kinome scan assay
showed that AAPK-25 was remarkably selective to both Aurora and PLK
families. The relevant genome pathways were also depicted by microarray
based gene expression analysis. Furthermore, validated from a set
of in vitro and in vivo studies, AAPK-25 significantly inhibited the
development of the colon cancer growth and prolonged the median survival
time at the end of the administration (p < 0.05).
To sum up, AAPK-25 has a great potential to be developed for a chemotherapeutic
agent in clinical use.