Peptide and peptide mimetic binding antagonists of polo-like kinase 1 polo box domain and methods of use
Inventors
Qian, Wenjian • Park, Jung Eun • Lai, Christopher C. • Kelley, James A. • Lee, Kyung S. • Burke, Jr., Terrence R.
Assignees
US Department of Health and Human Services
Publication Number
US-10047122-B2
Publication Date
2018-08-14
Expiration Date
2034-03-14
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Abstract
The invention provides novel compounds that may serve as anticancer therapeutics. The compounds of the invention bind to polo-like kinases through the polo-box domain. In certain embodiments, the compounds of the invention are POM-protected peptide derivatives. The use of cationic bis-alkyl his residues in combination with a mono POM-protected phophoryl group results in a peptide possessing an overall neutral charge. The peptide derivatives of the invention have achieved both good efficacy and an enhanced bioavailability. The invention also provides methods of use, compositions, and kits thereof. Further, the invention provides a novel method of design and/or synthesis of phosphoryl-derived peptide derivatives useful as therapeutic agents.
Core Innovation
The invention provides novel compounds, specifically peptide and peptide-mimetic derivatives, that bind to polo-like kinase 1 (Plk1) through its polo-box domain (PBD). These compounds are designed to serve as anticancer therapeutics by inhibiting Plk1 function, which is critical in cell proliferation and tumorigenesis. The problem addressed is the limited bioavailability and efficacy in whole-cell systems of existing PBD-binding peptides, which is attributed to the di-anionic charge of the phosphoryl functionalities leading to poor solubility and membrane transport.
The present invention overcomes this by designing peptide derivatives with neutral overall charge using cationic bis-alkyl histidine residues in combination with mono-pivaloyloxymethyl (POM)-protected phosphoryl groups. This design achieves enhanced cellular uptake and good efficacy. The invention further provides methods for design and synthesis of phosphoryl-derived peptide derivatives, compositions including pharmaceutically acceptable salts and carriers, and kits for use in the prevention, amelioration, or treatment of hyperproliferative disorders such as cancer.
Claims Coverage
The patent claims cover a compound class defined by specific structural formulas and peptide derivatives, with multiple inventive features related to chemical composition, protection groups, and therapeutic uses.
Compounds comprising POM-protected peptide derivatives binding the polo-box domain of Plk1
The compounds are peptide derivatives which bind to the Plk1 PBD, containing 4-5 residue peptides with pThr, pSer, or Pmab residues, and are mono- or di-POM protected to improve bioavailability. The general Formula (I), (II), and several sub-formulas define their chemical structure with various substituents.
Neutralization of net anionic charge in peptides via cationic bis-alkyl His residues and POM protection
Peptide derivatives include cationic bis-alkyl histidine residues combined with mono-POM-protected phosphoryl groups, creating peptides with overall neutral charge for enhanced cellular uptake and efficacy.
Methods for preparation of peptide derivatives using POM-protected amino acid analogues
The invention provides methods involving phosphoryl derivatization protocols and the use of novel POM-protected amino acid analogues (pThr, pSer, or Pmab) as intermediates or building blocks in peptide synthesis.
Pharmaceutical compositions, methods of use, and kits containing the compounds
Compositions include pharmaceutically acceptable carriers for treatment or prevention of hyperproliferative disorders, especially cancers. Kits comprise compounds and instructions for use. Uses include treatment of various cancers and optionally for AIDS with HIV Tat-tagged compounds.
The claims comprehensively cover novel peptide derivatives that bind selectively to Plk1 PBD with enhanced bioavailability via POM protection and bis-alkyl histidine residues, methods of preparing such compounds, and their therapeutic applications in treating hyperproliferative disorders such as cancer.
Stated Advantages
The peptide derivatives achieve enhanced bioavailability by neutralizing anionic charge through POM protection and cationic bis-alkyl His residues.
The compounds demonstrate good efficacy in cellular studies including effective mitotic block and inhibition of cell growth.
The compounds provide a novel anticancer mode by down-regulating oncogenic Plk1 through spatial dis-regulation via blocking its PBD function.
Documented Applications
The compounds are explicitly described for use in prevention, amelioration, or treatment of hyperproliferative disorders including a wide range of cancers such as Acute Lymphoblastic Leukemia, Breast Cancer, Colon Cancer, Lung Cancer, Melanoma, and others.
The compounds can also be used for treatment of acquired immunodeficiency syndrome (AIDS), with embodiments involving tagging compounds with HIV Tat-sequences to inhibit HIV budding.
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