Several inhibitors of the Plk1 Polo-Box Domain turn out to be non-specific protein alkylators

Cell Cycle
V Archambault, Karine Normandin

Abstract

For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD). Selective chemical inhibitors of the PBD would constitute tools to probe for PBD-dependent functions of Plk1 and could be advantageous in cancer therapy. The discovery of Poloxin and thymoquinone as PBD inhibitors indicated that small, cell-permeable chemical inhibitors could be identified. Other efforts followed, including ours, reporting additional molecules capable of blocking the PBD. It is now clear that, unfortunately, most of these compounds are non-specific protein alkylators (defined here as groups covalently added via a carbon) that have little or no potential for the development of real Plk1 PBD-specific drugs. This situation should be minded by biologists potentially interested in using these compoun...Continue Reading

References

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Citations

Aug 28, 2018·Journal of Biomolecular Structure & Dynamics·Maaged Abdullah, Lalitha Guruprasad
Jul 13, 2019·Future Medicinal Chemistry·Inas Elsayed, Xiaosheng Wang
Jul 9, 2020·Future Medicinal Chemistry·Iryna Kolosenko, Caroline Palm-Apergi
Aug 15, 2018·Oncogene·Oksana GoroshchukCaroline Palm-Apergi
Feb 21, 2019·Blood Advances·Céline MoisonGuy Sauvageau
Nov 12, 2020·Journal of Medicinal Chemistry·Celeste N AlverezKyung S Lee
Aug 30, 2021·Biochemical Pharmacology·Styliani IliakiInna S Afonina

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Methods Mentioned

BETA
pulldown
BRET
NMR
circular dichroism

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