Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells

PLK1, polo-like kinase 1, is a central
player regulating mitosis.
Inhibition of the subcellular localization and kinase activity of
PLK1 through the PBD, polo-box domain, is a viable alternative to
ATP-competitive inhibitors, for which the development of resistance
and inhibition of related PLK family members are concerns. We describe
novel nonpeptidic PBD-binding inhibitors, termed abbapolins, identified
through successful application of the REPLACE strategy and demonstrate
their potent antiproliferative activity in prostate tumors and other
cell lines. Furthermore, abbapolins show PLK1-specific binding and
inhibitory activity, as measured by a cellular thermal shift assay
and an ability to block phosphorylation of TCTP, a validated target
of PLK1-mediated kinase activity. Additional evidence for engagement
of PLK1 was obtained through the unique observation that abbapolins
induce PLK1 degradation in a manner that closely matches antiproliferative
activity. Moreover, abbapolins demonstrate antiproliferative activity
in cells that are dramatically resistant to ATP-competitive PLK1 inhibitors.