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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 
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
 0022-2623 
Issue Date
2022-01
MeSH
Animals ; Cell Cycle Proteins / antagonists & inhibitors* ; Cell Cycle Proteins / chemistry ; Cell Cycle Proteins / metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Peptides, Cyclic / chemical synthesis ; Peptides, Cyclic / metabolism ; Peptides, Cyclic / pharmacology* ; Peptidomimetics / chemical synthesis ; Peptidomimetics / metabolism ; Peptidomimetics / pharmacology* ; Protein Binding ; Protein Domains ; Protein Kinase Inhibitors / chemical synthesis ; Protein Kinase Inhibitors / metabolism ; Protein Kinase Inhibitors / pharmacology* ; Protein Serine-Threonine Kinases / antagonists & inhibitors* ; Protein Serine-Threonine Kinases / chemistry ; Protein Serine-Threonine Kinases / metabolism ; Proto-Oncogene Proteins / antagonists & inhibitors* ; Proto-Oncogene Proteins / chemistry ; Proto-Oncogene Proteins / metabolism ; Structure-Activity Relationship ; Zebrafish
Abstract
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.
Full Text
https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01359
DOI
10.1021/acs.jmedchem.1c01359
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188018
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