دورية أكاديمية
Targeting subcellular localization through the polo-box domain: non-ATP competitive inhibitors recapitulate a PLK1 phenotype.
| العنوان: | Targeting subcellular localization through the polo-box domain: non-ATP competitive inhibitors recapitulate a PLK1 phenotype. |
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| المؤلفون: | McInnes C; Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA. mcinnes@sccp.sc.edu, Estes K, Baxter M, Yang Z, Farag DB, Johnston P, Lazo JS, Wang J, Wyatt MD |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2012 Aug; Vol. 11 (8), pp. 1683-92. Date of Electronic Publication: 2012 Jul 30. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Phenotype*, Cell Cycle Proteins/*metabolism , Peptides/*pharmacology , Protein Interaction Domains and Motifs/*drug effects , Protein Serine-Threonine Kinases/*metabolism , Proto-Oncogene Proteins/*metabolism, Apoptosis/drug effects ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/chemistry ; HeLa Cells ; Humans ; Intracellular Space/metabolism ; Mitosis/drug effects ; Molecular Docking Simulation ; Peptides/chemistry ; Peptides/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/chemistry ; Protein Transport/drug effects ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/chemistry ; Structure-Activity Relationship ; cdc25 Phosphatases/chemistry ; Polo-Like Kinase 1 |
| مستخلص: | The polo-box domain (PBD) has critical roles in the mitotic functions of polo-like kinase 1 (PLK1). The replacement with partial ligand alternative through computational enrichment (REPLACE) strategy to develop inhibitors of protein-protein interactions has identified alternatives for the N-terminal tripeptide of a Cdc25C substrate. In addition, a peptide structure-activity relationship described key determinants and novel information useful for drug design. Fragment-ligated inhibitory peptides (FLIP) were generated with comparable affinity to peptide PBD inhibitors and possessed antiproliferative phenotypes in cells consistent with the observed decrease in PLK1 centrosomal localization. These FLIPs showed evidence of enhanced PLK1 inhibition in cells relative to peptides and induced monopolar and multipolar spindles, which stands in contrast to previously reported small-molecule PBD inhibitors that display phenotypes only partially representative of PLK1 knockdown. Progress obtained applying REPLACE validates this approach for identifying fragment alternatives for determinants of the Cdc25C-binding motif and extends its applicability of the strategy for discovering protein-protein interaction inhibitors. In addition, the described PBD inhibitors retain high specificity for PLK1 over PLK3 and therefore show promise as isotype selective, non-ATP competitive kinase inhibitors that provide new impetus for the development of PLK1-selective antitumor therapeutics. |
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| معلومات مُعتمدة: | R25 GM076277 United States GM NIGMS NIH HHS; UL1 TR000005 United States TR NCATS NIH HHS; UL1 TR000062 United States TR NCATS NIH HHS; UL1 RR029882 United States RR NCRR NIH HHS; UL1RR029882 United States RR NCRR NIH HHS |
| المشرفين على المادة: | 0 (Cell Cycle Proteins) 0 (Peptides) 0 (Proto-Oncogene Proteins) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 3.1.3.48 (cdc25 Phosphatases) |
| تواريخ الأحداث: | Date Created: 20120801 Date Completed: 20121217 Latest Revision: 20231213 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC3711794 |
| DOI: | 10.1158/1535-7163.MCT-12-0006-T |
| PMID: | 22848093 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
|---|---|
| DOI: | 10.1158/1535-7163.MCT-12-0006-T |