Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors
Name
nihms-1510482.pdf
Description
Accepted version
Size
570.84 KB
Format
Adobe PDF
Checksum (MD5)
845b5a8db052f987d5c9d3e5630fd119
Author(s)
Grant, Robert A.
Yaffe, Michael B.
Date Issued
October 2018
Journal
Bioorganic & Medicinal Chemistry Letters
Publisher
Elsevier BV
Citation
Hymel, David et al. "Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors." Bioorganic & Medicinal Chemistry Letters 28 (2018):3202-3205 © 2018 The Author(s)
Version
Author's final manuscript
Abstract
Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLH∗SpT (2a) (where H∗ indicates the presence of a –(CH2)8Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. The resulting macrocycles are highly potent in biochemical assays and maintain good target selectivity for the Plk1 PBD versus the PBDs of Plk2 and Plk3. Importantly, as exemplified by 5d, our current approach permits deletion of the N-terminal “Pro-Leu” motif to yield tripeptide ligands with decreased molecular weight, which retain high affinity and show improved target selectivity. These findings could fundamentally impact the future development of peptide macrocycles in general and Plk1 PBD-binding peptide mimetics in particular.
Subjects
Organic Chemistry
Clinical Biochemistry
Molecular Medicine
Biochemistry
Molecular Biology
Drug Discovery
Pharmaceutical Science
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.bmcl.2018.08.018
