Discovery of Cdc25A Lead Inhibitors with a Novel Chemotype by Virtual Screening: Application of Pharmacophore Modeling Based on a Training Set with a Limited Number of Unique Components

Abstract Cdc25 phosphatase was studied as an attractive target for cancer therapy. Multiple pharmacophore models with the unique core features of classic quinone inhibitors and those of novel inhibitors were used to discover a novel lead inhibitor. A total of 21 compounds with qualified physical properties were screened from the Maybridge HitFinder database containing 14 400 compounds by pharmacophore models. Four compounds were found to inhibit Cdc25A activity by more than 50 % at a concentration of 100 μ m . Among these compounds, KM10389 ( N ‐{2‐[(furan‐2‐ylmethyl)thio]ethyl}‐2‐[(4‐hydroxy‐6‐propylpyrimidin‐2‐yl)thio]acetamide) showed high inhibitory activity with an IC 50 value of 7.9 μ m . Selective cytotoxicity toward HeLa cells was observed with an IC 50 value of 66.3 μ m , whereas the IC 50 value for HEK293 cells was higher than 100 μ m . Blocking of the G1/S transition was also observed for HeLa cells in the presence of the compound by increasing the G1 phase by 16.15 %. Together with compounds HTS02435 and HTS01205, a novel lead inhibitor structure was identified and analyzed by a molecular docking study. The implication of virtual screening by using different pharmacophore models representing the different features is fully discussed.