Structure-Guided Discovery of Selective Polo-Like Kinase 3 Inhibitors

Polo-like kinases (PLKs) are a family of closely related serine/threonine kinases responsible for regulating cell cycle processes and proliferation. While PLK1 inhibitors have led to clinical candidates for oncology, the biological function of other PLKs is relatively unknown, in part, because there is a dearth of selective tool compounds. Herein we report the parallel medicinal chemistry (PMC) and structure-assisted discovery of potent and selective PLK3 inhibitors with favorable drug-like properties. We employed computational tools to reveal subtly different pharmacophore features within homologous binding sites of PLKs. These preferences were then exploited via a PMC approach starting from in-house high-throughput screening hits, resulting in selective chemical probes that help elucidate the complexities of PLK biology. Further, by profiling compounds with a spectrum of PLK selectivities, our work demonstrates the relationship between inhibition of specific PLK isoforms and resulting toxicities.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2026-05-12
DOI
https://doi.org/10.1021/acsmedchemlett.5c00687
Primary Topic
Microtubule and mitosis dynamics
Type
article
Field-Weighted Citation Impact
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article

Structure-Guided Discovery of Selective Polo-Like Kinase 3 Inhibitors

Gabrielle Lovett, Mikayla Mclaughlin, J. Jasti, Theresa Dickinson et al.
ACS Medicinal Chemistry Letters
Microtubule and mitosis dynamics
article

Structure-Guided Discovery of Selective Polo-Like Kinase 3 Inhibitors

Gabrielle Lovett, Mikayla Mclaughlin, J. Jasti, Theresa Dickinson, Jeremy W. Mason, Karen J. Coffman, Veroniquè Frattini, George S. Tria, Michel F. Guiraldelli, Ingrid A. Stock, Amanda Pecora, Jennifer A. Young, Xinjun Hou, Matthew C. Robinson, Yanfei Guan, Jeremy L. Yap, Nathaniel T. Kenton, Joseph Tucker, Lisa Marroquin, Roger Machin-Rivera, Andy Chen, Jamie DaSilva, David Boe, Christopher L. McClendon, Alpha A. Lee, Lei Zhang, Jamison Tuttle
article en

Abstract

Polo-like kinases (PLKs) are a family of closely related serine/threonine kinases responsible for regulating cell cycle processes and proliferation. While PLK1 inhibitors have led to clinical candidates for oncology, the biological function of other PLKs is relatively unknown, in part, because there is a dearth of selective tool compounds. Herein we report the parallel medicinal chemistry (PMC) and structure-assisted discovery of potent and selective PLK3 inhibitors with favorable drug-like properties. We employed computational tools to reveal subtly different pharmacophore features within homologous binding sites of PLKs. These preferences were then exploited via a PMC approach starting from in-house high-throughput screening hits, resulting in selective chemical probes that help elucidate the complexities of PLK biology. Further, by profiling compounds with a spectrum of PLK selectivities, our work demonstrates the relationship between inhibition of specific PLK isoforms and resulting toxicities.

ACS Medicinal Chemistry Letters
Pfizer (United States) (US), Post University (US), PRX Research
Openalex Percentile: Top 6%
Microtubule and mitosis dynamics
DOIOpen Access PDFOpenAlex
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