Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1
Authors
SeongShick Ryu ; Jung-Eun Park ; Young Jin Ham ; Daniel C Lim ; Nicholas P Kwiatkowski ; Do-Hee Kim ; Debabrata Bhunia ; Nam Doo Kim ; Michael B Yaffe ; Woolim Son ; Namkyoung Kim ; Tae-Ik Choi ; Puspanjali Swain ; Cheol-Hee Kim ; Jin-Young Lee ; Nathanael S Gray ; Kyung S Lee ; Taebo Sim
Citation
JOURNAL OF MEDICINAL CHEMISTRY, Vol.65(3) : 1915-1932, 2022-01
The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16e on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h, a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a. Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.