Development of a High-Throughput Assay for Inhibitors of the Polo-Box Domain of Polo-Like Kinase 1 Based on Time-Resolved Fluorescence Energy Transfer

Kim, Tae Gi; Lee, Mi Young; Kim, Ka-Ul; Lee, Jeong Hyun; Park, Chi Hoon; Lee, Byung Ho; Oh, Kwang‐Seok

doi:10.1248/bpb.b17-00283

Cited by 4 publications

(1 citation statement)

References 30 publications

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“…Over the years, various Plk1 PBD inhibitors were generated by either derivatizing the well-characterized minimal phosphopeptide, PLHSpT 6a , or isolating small molecules interfering with Plk1 PBD-dependent PPI. , However, although peptide-derived inhibitors provide valuable insights into the binding interface of Plk1 PBD-dependent interactions, whether they can serve as a lead for developing anti-PBD agents is disputable, largely because of their poor permeability and limited bioavailability . In addition, although multiple small molecule inhibitors targeting the Plk1 PBD were reported, most exhibit a low level (IC 50 of 50–1000 μM) of anti-Plk1 activity in cell-based assays, − while others are not sufficiently characterized at the cellular level. − …”

Section: Introductionmentioning

confidence: 99%

Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1

et al. 2020

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As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The Cterminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein−protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-a]quinazolin-5(1H)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure−activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT (K d ∼ 450 nM). In addition, S-methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.

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