By a process involving initial screening of a set of 87 aldehydes using an oxime ligation-based strategy, we were able to achieve a several-fold affinity enhancement over one of the most potent previously known polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors. This improved binding may result by accessing a newly identified auxiliary region proximal to a key hydrophobic cryptic pocket on the surface of the protein. Our findings could have general applicability to the design of PBD-binding antagonists.
Cover design by Joseph Myer
Xue Zhi Zhao, David Hymel and Terrence R. Burke, Jr. in Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5009-5012.