17445-57-7Relevant articles and documents
Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1
Ryu, Seongshick,Park, Jung-Eun,Ham, Young Jin,Lim, Daniel C.,Kwiatkowski, Nicholas P.,Kim, Do-Hee,Bhunia, Debabrata,Kim, Nam Doo,Yaffe, Michael B.,Son, Woolim,Kim, Namkyoung,Choi, Tae-Ik,Swain, Puspanjali,Kim, Cheol-Hee,Lee, Jin-Young,Gray, Nathanael S.,Lee, Kyung S.,Sim, Taebo
supporting information, p. 1915 - 1932 (2022/02/07)
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.
