Polo-like kinase 1 (PLK1) is a serine/threonine kinase which functions in mitosis and cytokinesis and as such is a target for anti-cancer therapeutics. Here we describe the discovery of 2 classes of potent PLK1 inhibitors: namely, the [1,2,4]triazolo[1,5-a]pyridine series (TPs) and the 1H-pyrazolo[3,4-d]pyrimidine series (PZPs). 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 5/6- ring systems bind in opposing orientations. Our calculations demonstrate that intramolecular sterics originating from the inhibitor core in combination with steric effects from the PLK1 binding pocket contribute to the observed conformational differences.

Potent [1,2,4]triazolo[1,5-a]pyridine and 1H-pyrazolo[3,4-d]pyrimidine inhibitors of polo-like kinase 1 and the structural basis for divergent SAR between the series

248th National Meeting (2014)

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