Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors

Bioorganic & Medicinal Chemistry Letters
David HymelTerrence R Burke

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.

References

Jul 15, 2009·Nature Structural & Molecular Biology·Sang-Moon YunKyung S Lee
Jul 19, 2011·Nature Chemical Biology·Fa LiuTerrence R Burke
May 10, 2012·Chembiochem : a European Journal of Chemical Biology·Fa LiuTerrence R Burke
Apr 23, 2014·Bioorganic & Medicinal Chemistry Letters·Wenxing GuoHaitao Ji
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Mar 14, 2017·Bioorganic & Medicinal Chemistry·Xue Zhi ZhaoTerrence R Burke

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Citations

Apr 25, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xue Zhi ZhaoTerrence R Burke
Mar 26, 2021·European Journal of Medicinal Chemistry·Zheng ZhangTingting Liu
Apr 13, 2021·Frontiers in Cell and Developmental Biology·Dazhong Xu, Cen Li
Jan 15, 2022·Journal of Medicinal Chemistry·SeongShick RyuTaebo Sim

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