National Institutes of Health, a Component of the US Dept. of Health & Human Services

The United States of America As Represented by the Department of Health

Georgetown University

The United States of America As Represented by the Secretary of

Terrence R Burke, Jr

Yang Gao

Zhu-jun Yao

Donald P Bottaro

Zhen-Dan Shi

Benjamin B Lim

Kyung S Lee

Yves Pommier

Dajun Yang

Stephen H Hughes

Christophe Marchand

Alessio Giubellino

Jesus V Soriano

Chang-Qing Wei

Diane E Breckenridge

Safiye N Atabey

Mark S Smyth

Barry Johnson

Mathieu Metifiot

Steven Smith

Xue Zhi Zhao

Jung-Eun Park

Fa Liu

Kenner C Rice

Thomas U Hofer

Christoph Rader

C Richter King

Johannes H Voigt

Stuart H Yuspa

James A Kelley

Candace B Pert

Miki Akamatsu

William C Eckelman

Gagani P Athauda

Nelly Tan

Marc Nicklaus

Megan Peach

Michael A Channing

Steven M Larson

David T Hymel

Caroline Stanwell

Peter R Roller

Xinjian Yan

Hemanta K Kole

Bin Ye

Kohei Tsuji

Wenjian Qian

Sang-Uk Kang

Jung Eun Park

Christopher C Lai

Joshua Thomas

Sarah Choyke

The description provides novel compounds that may serve as anticancer therapeutics. The compounds of the description bind to polo-like kinases through the polo-box domain. The peptide derivatives of the description have achieved improved efficacy in biochemical assays against Plk1. Exemplary compounds of the description include macrocyclic peptidomimetics with high affinity and selectivity for polo-like kinases, which may provide the basis for a new genre of anticancer therapeutics. Other exemplary compounds of the description include bi-valent compounds with that bind to polo-like kinases through both kinase domain and polo-box domain simultaneously by incorporating additional moieties that target Plk1 kinase domain, which significantly enhances affinitity relative and may provide the basis for a new genre of anticancer therapeutics. The description also provides methods of use, methods of preparation, compositions, and kits thereof. Further, the description provides a novel method of design and/or synthesis of phosphoryl-derived peptide derivatives useful as therapeutic agents.

Peptide and peptide mimetic binding antagonists of polo-like kinase 1 polo box domain and methods of use

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.

Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use

A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is N, C(OH), or CH;Y is H or OH;each of Z-Zis independently H or halogen;Ris H, OH, NH, NHR, NRRor R;R, R, and Ris each independently H, halogen, OR, R, NHR, NRR, COR, CONRR, SONRR, or Rand Rtogether with the carbon atoms to which Rand Rare attached form an optionally-substituted carbocycle or optionally-substituted heterocycle; andRand Ris each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or Rand Rtogether with the nitrogen to which Rand Rare attached form an optionally-substituted heterocycle.

Compounds for inhibiting drug-resistant strains of HIV-1 integrase

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.

Found in various eukaryotic organisms, polo-like kinases (collectively, Plks) are a conserved subfamily of Ser/Thr protein kinases that play critical roles in cell proliferation. Provided herein are compounds that specifically inhibit the activity of Plks, specifically Plk1. Further provided herein are methods for use of the compounds for the treatment of hyperproliferative disorders, particularly cancer. Also provided are uses of the compounds for the preparation of a medicament.

The invention provides methods and compositions employing hybrid molecules of a synthetic molecule and antibody or antibody fragment comprising a selenocysteine residue, wherein the synthetic molecule is covalently linked to the antibody or antibody fragment at the selenocysteine residue. The invention also provides a composition comprising a hybrid molecule as described above and a pharmaceutically acceptable carrier. The invention further provides for methods of making the hybrid molecules, and methods of using the hybrid molecule described above to inhibit cell surface receptor binding.

Selenocysteine mediated hybrid antibody molecules

Derivatives and analogs of inhibitors of receptor tyrosine kinase c-Met, pharmaceutical compositions containing derivatives and analogs of c-Met inhibitors are provided. Methods of making derivatives and analogs of c-Met inhibitors and methods of use thereof are provided. 

Compositions and methods for inhibition of hepatocyte growth factor receptor c-Met signaling

Disclosed are methods of inhibiting cell motility, for example, by inhibiting the binding between an intracellular transducer and a receptor protein tyrosine kinase, and more particularly by inhibiting hepatocyte growth factor (HGF) induced cell motility. The present invention also provides a method of inhibiting angiogenesis. The methods of the present invention employ peptides such as phosphotyrosyl mimetics. Also disclosed are methods of preventing and/or treating diseases, disorders, states, or conditions such as cancer, particularly metastatic cancer, for example, melanoma or prostate cancer, comprising administering to a mammal of interest one or more peptides of the present invention. Also disclosed are methods of blocking blocks HGF, VEGF, or bFGF-stimulated migration, cell proliferation, and formation of capillary-like structures.

Inhibition of cell motility, angiogenesis, and metastasis

The present invention provides phenylalanine derivatives that inhibit SH2 domain binding with a phosphoprotein. These derivatives include compounds of the formula: W&#x2014;Y-(AA)-Z wherein n is 0 to 15; Y is a phenylalanyl radical having a phenyl ring, an amine end, and a carboxyl end, the phenyl ring having one or more substituents, e.g., hydroxyl, carboxyl, formyl, carboxyalkyl, carboxyalkyloxy, dicarboxyalkyl, dicarboxyalkyloxy, dicarboxyhaloalkyl, dicarboxyhaloalkyloxy, and phosphonoalkyl, or phosphonohaloalkyl; W is a moiety attached to the nitrogen of Y and is, e.g., alkylcarbonyl, oxalyl, alkylaminooxalyl, arylaminooxalyl, arylalkylaminooxalyl, or alkoxyoxalyl; AA is an amino acid, the amine end of which is attached to the carboxyl end of Y; and Z is an arylalkylamino or arylheterocyclyl alkylamino; or a salt thereof; with the proviso that W is not arylalkylamino when the phenyl ring of phenylalanyl contains a phosphonoalkyl or phosphonohaloalkyl substituent at a position para to the alkylamido group and the ortho and meta positions are unsubstituted. The present invention further provides precursors suitable for preparing the phenylalanine derivatives and a method for the preparation of the precursors. The present invention further provides conjugates comprising a precursor and a conjugant that are covalently linked. These conjugates have biological and/or pharmacological properties. 

Phenylanine derivatives

Disclosed are compounds represented by the formula: or a pharmaceutically acceptable salt or isomer thereof, wherein R-Rare as defined in the specification. These compounds are targeted for use as inhibitors of SH2 domain binding with a phosphoprotein, and are contemplated for use in a number of diseases including cancer. Also disclosed are pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

SH2 domain binding inhibitors

Disclosed are compounds for SH2 domain binding inhibition, for example, a compound of formula (I), wherein Ris a lipophile; R, in combination with the phenyl ring, is a phenylphosphate mimic group or a protected phenylphosphate mimic group; Ris hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of Rmay be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; Ris a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. The conformationally compounds provide enhanced binding affinity with SH2 domain protein. Also disclosed are a pharmaceutical compositions and a method for inhibiting an SH2 domain from binding with a phosphoprotein.

Disclosed herein are phenylalanine derivative compounds of the following formulaW&#x2014;Y&#x2014;(AA)&#x2014;Zwherein Y is a phenylalanyl radical, AA is an amino acid, n is an integer of 1 to 15, and substituent variables W and Z are as described herein. The compounds can be used to inhibit SH2 binding with phosphoproteins, and to inhibit proliferation of tumor cells.

Phenylalanine derivatives

Disclosed are methods of inhibiting cell motility, for example, by inhibiting the binding between an intracellular transducer and a receptor protein tyrosine kinase, and more particularly by inhibiting hepatocyte growth factor (HGF) induced cell motility. The present invention also provides a method of inhibiting angiogenesis. The methods of the present invention employ peptides such as phosphotyrosyl mimetics. The present invention further provides methods of preventing and/or treating diseases, disorders, states, or conditions such as cancer, particularly metastatic cancer comprising administering to a mammal of interest one or more peptides of the present invention. Also disclosed are methods of blocking HGF, VEGF, or bFGF-stimulated migration, cell proliferation, and formation of capillary-like structures 

Inhibition of cell motility and angiogenesis by inhibitors of Grb2-SH2-domain

Disclosed are compounds for SH2 domain binding inhibition. For example, disclosed is a compound of formula (I)wherein Ris a lipophile; R, in combination with the phenyl ring, forms a phenylphosphate mimic group or a protected phenylphosphate mimic group; Ris hydrogen, azido, amino, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, or alkylcarbonylamino, wherein the alkyl portion of Rmay be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, aminoalkyl, alkyl, alkoxy, and keto; Ris a linker; AA is an amino acid; and n is 1 to 6; or a salt thereof. Also disclosed are a pharmaceutical composition, a method for inhibiting an SH2 domain from binding with a phosphoprotein and a method of treating breast cancer.

Growing community of inventors

Bethesda, MD, United States of America

Terrence R Burke, Jr