Potent triazolopyridine and pyrazolopyrimidine inhibitors of PLK1 and the structural basis for divergent SAR between the series

Polo-like kinase 1 (PLK1) is a serine/threonine kinase which functions in mitosis and cytokinesis and as such is a target for anticancer therapeutics. Here we describe the discovery of 2 classes of potent PLK1 inhibitors: namely, the [1,2,4]triazolo[1,5-a]pyridine series and the 1H-pyrazolo[3,4-d]pyrimidine series. In this poster, we will show SAR comparisons and X-ray crystallographic analysis for the two series. The two chemical series have highly similar R-group trajectories and interactions, however the 5/6ring systems bind in opposing orientations. We have identified, and will discuss, how intramolecular sterics originating from the inhibitor core in combination with steric effects from the PLK1 binding pocket contribute to the observed conformational differences.