Design, synthesis and evaluation of peptidomimetics targeting the polo-box domain of polo-like kinase 1 / 中国药科大学学报

@#To identify novel inhibitors targeting the polo-box domain of polo-like kinase 1 (Plk1 PBD), a series of new peptidomimetics (7a-7u) without phosphate group were designed and synthesized, where the phosphate group in the structure of the selective Plk1 PBD inhibitor PLHSpT was replaced by the carboxyl group, and the unnatural amino acids were applied for further modification and optimization. The 21 peptidomimetic compounds designed and synthesized had a strong inhibitory effect on Plk1 PBD, of which compound 7l highly selectively inhibited Plk1 PBD with IC50 of 0.285 μmol/L. The growth inhibition effect of HeLa tumor cell lines in vitro was better than that of compounds containing phosphate group. Moreover, the stability of the compound in rat plasma was improved by unnatural amino acids. Thus it is proved that selective Plk1 PBD inhibitor with improved characters can be obtained by replacing the phosphate group with a carboxyl group and restructuring the peptide chain.

Screening of small molecule inhibitors for PLK1 PBD and evaluation of antitumor activities / 药学学报

With the method of fluorescence polarization (FP), we screened small molecule inhibitors for PLK1 PBD to identify the lead compounds for antitumor drugs. FP led to the identification of a potent hit, F083-0063, whose inhibition rate was (99.7±0.4)% at 10 μg·mL-1. The IC50 was calculated to be 1.9±0.1 μmol·L-1 using Graphpad Prism 5. The effect of the compound on cells' multiplication was measured by MTT assay which showed that F083-0063 inhibited the proliferation of many tumor cell lines. Flow cytometry analysis indicated that the F083-0063 promoted cell apoptosis and induced cell G2/M arrest. Migration abilities of cells, evaluated using scratch test, increased significantly in the presence of F083-0063 with the mi-gration rate as low as (37.6±0.7)% at 20 μmol·L-1. Molecular linkage technique found F083-0063 had good affinity with PLK1 PBD. The results of Western blotting showed that the expression of cyclin-dependent proteins was increased after treatment with F083-0063. In summary, F083-0063 has an antitumor activity and is expected to be an antitumor lead compound targeting PLK1 PBD.