Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use
Inventors
Burke, Jr., Terrence R. • Liu, Fa • Lee, Kyung S. • Park, Jung-Eun
Assignees
US Department of Health and Human Services
Publication Number
US-10266565-B2
Publication Date
2019-04-23
Expiration Date
2032-04-12
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Abstract
Novel compounds are provided that bind to polo-like kinases through the polo-box domain. In certain embodiments, the novel compounds are PEGylated peptides. The PEGylated peptides in accordance with the invention demonstrate high PBD-binding affinity. In certain embodiments, the PEGylated peptides have also achieved activities in whole cell systems. The invention also provides compounds that bind polo-like kinases through the polo-box domain and possess reduced anionic charge. Further provided are methods of design and/or synthesis of the PEGylated peptides and methods of use thereof. The invention provides methods of use of the compounds and methods of synthesis of the compounds.
Core Innovation
The invention provides novel compounds that bind to polo-like kinases through the polo-box domain (PBD), particularly peptide-mimetic ligands of polo-like kinase 1 (Plk1), a regulator of mitotic events and cellular proliferative potential. These compounds include PEGylated peptides that demonstrate high PBD-binding affinity and have achieved activities in whole cell systems. Further compounds possess reduced anionic charge to enhance uptake into whole cells, addressing bioavailability challenges.
The problem being solved arises from the difficulty in designing PBD-binding peptides with improved pharmaceutical properties, such as increased bioavailability, solubility, and membrane transport. Although peptides like PLHSpT specifically interact with Plk1 PBD with high affinity, their poor bioavailability prevents effective activity in whole-cell systems. Additionally, current Plk1 inhibitors often lack specificity due to structural similarities among catalytic domains in Plks and related kinases, thus novel inhibitors targeting the PBD are needed for selective Plk1 targeting.
Claims Coverage
The patent includes one independent claim focusing on compounds of specific chemical formulae binding to the polo-like kinase 1 PBD, and compositions and kits comprising such compounds, outlining their structural and functional features.
Compounds of defined chemical structure with PEGylated peptide moiety
The invention provides compounds of formulae, including Formula (a), characterized by a PEG moiety linked to peptide derivatives with variations in substituents including alkyl groups, heterocycles, and macrocyclic ring formations, optionally substituted by diverse groups such as aryl, heteroaryl, halogen, and amino groups. The compounds incorporate amino acid moieties such as Leu, His, or Gln, and may include pharmaceutically acceptable salts or stereoisomers.
Methods of use and compositions for prevention or treatment of hyperproliferative disorders
Compounds of the invention can be formulated with pharmaceutically acceptable carriers into compositions for use as medicaments intended for prevention, amelioration, or treatment of hyperproliferative disorders such as cancer, with provision for kit formulations containing the compounds and instructions for use.
Chemical libraries and kits containing the compounds
The invention includes chemical libraries comprising two or more compounds of defined formulae and kits comprising at least one compound with instructions for use, enabling therapeutic or synthetic applications.
The claims cover chemically defined PEGylated peptides and derivatives that bind Plk1 PBD selectively, pharmaceutical compositions and kits thereof, and chemical libraries for therapeutic use and compound synthesis. The features focus on structural and substituent variability contributing to specific binding and bioavailability enhancement.
Stated Advantages
PEGylated peptides demonstrate enhanced whole-cell activity compared to non-PEGylated peptides, overcoming limited intracellular bioavailability due to poor solubility and membrane transport.
Compounds exhibit high binding affinity and specificity for the Plk1 PBD, enabling selective inhibition of Plk1 over related kinases Plk2 and Plk3.
Use of phosphatase-resistant p-Thr mimetic amino acids like Pmab confers stability against intracellular phosphatases, enhancing therapeutic potential.
Formation of a novel hydrophobic binding channel upon ligand binding indicates a new mode of interaction important for drug design.
Documented Applications
Use in prevention, amelioration, or treatment of hyperproliferative disorders such as cancer including a broad spectrum of tumor types.
Use in prevention, amelioration, or treatment of acquired immunodeficiency syndrome (AIDS), including via compounds tagged with HIV Tat sequence for inhibition of HIV budding.
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