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Phosphatase‐Stable Phosphoamino Acid Mimetics That Enhance Binding Affinities with the Polo‐Box Domain of Polo‐like Kinase 1
Author(s) -
Hymel David,
Burke Terrence R.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600574
Subject(s) - plk1 , affinities , peptidomimetic , binding affinities , chemistry , polo like kinase , phosphatase , phosphoserine , kinase , biochemistry , stereochemistry , peptide , phosphorylation , receptor , serine , cell cycle , cell
(2 S ,3 R )‐2‐Amino‐3‐methyl‐4‐phosphonobutanoic acid (Pmab) is a phosphatase‐stable analogue of phosphothreonine (pThr), which has been used in a variety of biological contexts. Among these applications are peptidomimetic ligands that bind to the polo‐box domain (PBD) of polo‐like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr‐containing peptides. However, Pmab is not widely used, because there are no direct, high‐yield preparations of suitably protected reagent. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3 R center. When incorporated into our peptidomimetic scaffold, these new Pmab analogues exhibit Plk1 PBD‐binding affinities that are several‐fold higher than Pmab, yet retain good selectivity for Plk1 relative to the PBDs of Plk2 and Plk3. These findings will significantly impact the future development of PBD‐binding inhibitors, as well as ligands directed against a broad spectrum of pThr‐dependent processes.