Praecis Pharmaceuticals, Inc.

Glaxosmithkline LLC

Christopher C Arico-Muendel

Malcolm L Gefter

Barry A Morgan

Richard W Wagner

Dennis R Benjamin

David I Israel

Malcolm J Kavarana

Matthew Clark

Stephen Paul Hale

Raksha A Acharya

Nils Jakob Vest Hansen

George J Franklin

Gary Olson

Gary Fred Musso

Christopher Self

Mark A Findeis

Charles Michael Cook

Lily Lee

Ethan R Signer

Kathryn Phillips

James Wakefield

Jens Birktoft

Michael Kelley

Paolo A Centrella

Jung-Ja Lee

Joseph Chin

Susan Molineaux

Neil J Hayward

Sonja Komar-Panicucci

Steffen Phillip Creaser

Steffan Phillip Creaser

Sonja A Komar

Paulo A Centrella

Nils Jakob Hansen

Mathew A Clark

The present invention provides a method of synthesizing libraries of molecules which include an encoding oligonucleotide tag.

Methods for synthesis of encoded libraries

The present invention provides a method for identifying a compound of interest by screening libraries of molecules which include an encoding oligonucleotide tag.

Methods for identifying compounds of interest using encoded libraries

The present invention provides methods of synthesizing libraries of molecules comprising a functional moiety which is operatively linked to an encoding oligonucleotide, wherein the encoding oligonucleotide comprises a capping sequence containing degenerate nucleotides. The methods generally include providing a solution comprising initiator compounds comprising an initial functional moiety comprising n building blocks which is operatively linked to an initial oligonucleotide; dividing the solution into reaction vessels; reacting the initiator compounds in each reaction vessel with a building block comprising a complementary reactive group to form a covalent bond; and reacting the initial oligonucleotide in each aliquot with a distinct incoming oligonucleotide in the presence of an enzyme which catalyzes the ligation of the incoming oligonucleotide and the initial oligonucleotide, under conditions suitable for enzymatic ligation of the incoming oligonucleotide and the initial oligonucleotide to form an encoding oligonucleotide.

The present invention provides methods of synthesizing a molecule comprising a functional moiety which is operatively linked to an encoding oligonucleotide. The methods include providing an initiator compound comprising an initial functional moiety comprising n building blocks, wherein the initial functional moiety comprises at least one reactive group, and is operatively linked to an initial oligonucleotide; reacting the initiator compound with a building block comprising at least one complementary reactive group, under conditions suitable for reaction of the complementary reactive group to form a covalent bond; and reacting the initial oligonucleotide with an incoming oligonucleotide corresponding to the building block in the presence of an enzyme which catalyzes ligation of the initial oligonucleotide and the incoming oligonucleotide, under conditions suitable for ligation of the incoming oligonucleotide and the initial oligonucleotide to form an encoding oligonucleotide.

The present invention provides methods of synthesizing libraries of molecules comprising a functional moiety which is operatively linked to an encoding oligonucleotide. The methods generally include providing a solution comprising initiator compounds comprising an initial functional moiety which comprises n building blocks which comprise at least one reactive group, which is operatively linked to an initial oligonucleotide; dividing the solution into reaction vessels; reacting the initiator compounds in each reaction vessel with a building block comprising a complementary reactive group to form a covalent bond; and reacting the initial oligonucleotide in each aliquot with a distinct incoming oligonucleotide in the presence of an enzyme which catalyzes the ligation of the incoming oligonucleotide and the initial oligonucleotide, under conditions suitable for enzymatic ligation of the incoming oligonucleotide and the initial oligonucleotide to form an encoding oligonucleotide which identifies the structure of the functional moiety.

The present invention provides angiogenesis inhibitor compounds comprising a MetAP-2 inhibitory core coupled to a peptide, as well as pharmaceutical compositions comprising the angiogenesis inhibitor compounds and a pharmaceutically acceptable carrier. The present invention also provides methods of treating an angiogenic disease, e.g., cancer, in a subject by administering to the subject a therapeutically effective amount of one or more of the angiogenesis inhibitor compounds of the invention.

Therapeutic agents and methods of use thereof for the treatment of melanoma

The present invention provides methods of treating a lymphoma (e.g., a T-cell lymphoma or a B-cell lymphoma) in a subject by administering to the subject a therapeutically effective amount of one or more of the compounds of the invention, for example, compounds of formulae I and XV: 

Methionine aminopeptidase-2 inhibitors and methods of use thereof

Compounds that modulate natural &#x3b2; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &#x3b2; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3&#x2013;5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &#x3b2; amyloid peptide, preferably a retro-inverso isomer of A&#x3b2;. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &#x3b2;-amyloid peptide aggregation comprising D-amino acids

The present invention provides methods of treating an autoimmune disorder (e.g., lupus erythematosus, multiple sclerosis, myasthenia gravis, vasculitis and diabetes mellitus) in a subject by administering to the subject a therapeutically effective amount of one or more compounds of the invention.

Therapeutic agents and methods of use thereof for the modulation of angiogenesis

The present invention provides methods of treating, parasitic infections, thymoma, and lymphoid malignancies in a subject by administering to the subject a therapeutically effective amount of one or more of the compounds of the invention.

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr; . In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of &bgr;-amyloid peptide aggregation comprising D-amino acids

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr;,. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

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West Roxbury, MA, United States of America

Christopher C Arico-Muendel