ArticleCell chemical biology2017
Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS.
Article in Cell chemical biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
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- Article
- Mapping oncogenic protein interactions for precision medicine.International journal of cancer · 2022Review
- Structure-activity and mechanistic studies of non-peptidic inhibitors of the PLK1 polo box domain identified through REPLACE.European journal of medicinal chemistry · 2022Article
- Review
- Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics.Cancer research communications · 2021Article
- Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library.Cell chemical biology · 2021Article
- Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells.Journal of medicinal chemistry · 2021Article
- A new genre of fluorescence recovery assay to evaluate polo-like kinase 1 ATP-competitive inhibitors.Analytical methods : advancing methods and applications · 2020Article
- A programmable polymer library that enables the construction of stimuli-responsive nanocarriers containing logic gates.Nature chemistry · 2020Article
- Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.ACS omega · 2020Article
- A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation.Scientific reports · 2019Article
- Fast single-cell biochemistry: theory, open source microscopy and applications.Methods and applications in fluorescence · 2019Article
- Non-canonical cMet regulation by vimentin mediates Plk1 inhibitor-induced apoptosis.EMBO molecular medicine · 2019Article
- Polo-like kinase 1 inhibition in NSCLC: mechanism of action and emerging predictive biomarkers.Lung Cancer (Auckland, N.Z.) · 2019Article
- Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling.Cell chemical biology · 2018Article
- Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area.Current opinion in chemical biology · 2018Review
Corrections and comments
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Authors and funding
19 authors at 4 institutions in 1 country.
Funding
Abstract
Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis. PLK1 or PLK4 depletion recapitulates these cellular effects, as does PBD overexpression, corroborating Poloppin's mechanism of action. An optimized analog with favorable pharmacokinetics, Poloppin-II, is effective against KRAS-expressing cancer xenografts. Poloppin resistance develops less readily than to an ATP-competitive PLK1 inhibitor; moreover, cross-sensitivity persists. Poloppin sensitizes mutant KRAS-expressing cells to clinical inhibitors of c-MET, opening opportunities for combination therapy. Our findings exemplify the utility of small molecules modulating the protein-protein interactions of PLKs to therapeutically target mutant KRAS-expressing cancers.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.