Johns Hopkins University

The Rockefeller University

The State University of New York

The Wistar Institute

University of California

Mount Sinai School of Medicine

The Rockfeller University

Philip A Cole

Erin M Bowers

John Kuriyan

Ronen Marmorstein

David J Meyers

S Mariana Margarit

Ann Boriack-Sjodin

Ehab M Khalil

Xin Liu

Ling Wang

Chandrani Mukherjee

Jef D Boeke

Tom W Muir

Tapas Kumar Kundu

Robert G Roeder

Bradley P Barnett

Rhoda Myra Alani

Dolan Sondhi

Shonoi Ming

Raymond E Soccio

Ontario D Lau

Gai Yan

Jay Kalin

Polina Prusevich

Xuewu Zhang

Konstantine Severinov

Yousang Hwang

Aliya Courtney

Ronald A Kohanski

Ararat Abloogu

Keykavous Parang

A series of phenelzine analogs comprising a phenelzine scaffold linked to an aromatic moiety and their use as inhibitors of lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs) is provided. The presently disclosed phenelzine analogs exhibit potency and selectivity for LSD1 versus MAO and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Accordingly, the presently disclosed phenelzine analogs can be used to treat diseases, conditions, or disorders related to LSD1 and/or HDACs, including, but not limited to, cancers and neurodegenerative diseases.

Inhibitors of histone lysine specific demethylase (LSD1) and histone deacetylases (HDACS)

The present invention relates to a method for identifying compounds that modulate the activity of p300/CBP. Compounds of the invention are identified by designing or screening for a compound which binds to at least one amino acid residue of the newly identified lysine-CoA inhibitor binding site, L1 loop, electronegative pocket, or electronegative groove of the HAT domain of p300/CBP and testing the compound for its ability to modulate the activity of p300/CBP. Compositions and methods for preventing or treating diseases or disorders associated with p300/CBP are also provided as is a method for producing a semi-synthetic HAT domain.

Methods and compositions for modulating P300/CBP activity

The present invention provides methods for treating cancer comprising inhibiting the activity of p300/CBP histone acetyltransferase (HAT). Also provided are p300/CBP HAT inhibitors for treating a subject having cancer. In addition, the present invention includes biomarkers for p300/CBP HAT inhibition, which are used to i) monitor the effectiveness of cancer therapy, and ii) identify anti-cancer agents for use in combination therapy.

Use of histone acetyltransferase inhibitors as novel anti-cancer therapies

The invention provides inhibitors of ghrelin O-acyltransferase, and methods of making and using them. In some embodiments, the invention provides bisubstrate analog inhibitors of ghrelin O-acyltransferase, which can be effective in treating, for example, obesity and diabetes mellitus.

Methods for synthesis and uses of inhibitors of ghrelin O-acyltransferase as potential therapeutic agents for obesity and diabetes

The invention provides methods and compositions for the modulation of EGFR activity. In particular, inhibition of EGFR activation through an allosteric mechanism is discloses, as is a method for targeted drug discovery and design based on models of the three dimensional structure of the kinase domains of the protein dimers.

Inhibitors of the EGFR kinase targeting the asymmetric activating dimer interface

Protein kinase inhibitors have applications as anti-cancer therapeutic agents and biological tools in cell signalling. Potent and selective bisubstrate inhibitors for the insulin receptor tyrosine kinase are based on a phosphoryl transfer mechanism involving a dissociative transition state. One such inhibitor is synthesized by linking ATP&#x3b3;S to a peptide substrate analog via a two-carbon spacer. The compound is a high-affinity competitive inhibitor against both nucleotide and peptide substrate and shows a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirms the key design features inspired by a dissociative transition state, and reveal that the linker takes part in the octahedral coordination of an active site Mgion.

Bisbubstrate inhibitors of kinases

The present invention provides a method of cleaving a recombinantly expressed protein from an intein and ligating the protein to a peptide containing an N-terminal cysteine having an unoxidized sulfhydryl side chain which comprises contacting the protein with the peptide in a reaction solution comprising a conjugated thiophenol, thereby forming a C-terminal thioester of the recombinant protein which spontaneously rearranges intramolecularly to form an amide bond linking the protein to the peptide. The present invention also provides a method of producing a protein-chip composition comprising the steps of: (a) contacting a solid support chip containing an amine group with a peptide containing an N-terminal cysteine having an unoxidized sulfhydryl side chain thereby covalently linking the peptide to the solid support, forming a peptide-chip; and (b) contacting a recombinant protein having an intein domain with the peptide-chip of step (a) with a reaction solution containing a conjugated thiophenol, thereby forming a C-terminal thioester of the recombinant protein which spontaneously rearranges intramoleculaly to form an amide bond covalently linking the protein to the peptide-chip, thereby producing a protein-chip composition.

Methods of ligating expressed proteins

Histone acetyltransferase inhibitors, especially those that are differentiate between p300 and PCAF histone acetyltransferase; also therapeutic processes comprising their administration to humans.

Inhibitors of histone acetyltransferases (HATs) and uses thereof

A detailed three-dimensional structure for the complex formed between Ras and the Son of sevenless (Sos) protein is provided. Crystals of this complex are also included in the invention. The present invention farther provides procedures for identifying agents that can inhibit tumor proliferation through the use of rational drug design predicated on the crystals and crystallographic data disclosed.

Crystal of a Ras-Sos complex and methods of use thereof

A detailed three-dimensional structure for the complex formed between Ras and the Son of sevenless (Sos) protein is provided. Crystals of this complex are also included in the invention. The present invention further provides procedures for identifying agents that can inhibit tumor proliferation through the use of rational drug design predicated on the crystals and crystallographic data disclosed.

Crystal of a Ras-Sos complex

This invention is directed to a compound having the formula I. ##STR1## This invention is directed to a pharmaceutical composition comprising a compound which inhibits serotonin N-acetyltransferase having the formula I and a pharmaceutical acceptable carrier. The present invention relates to novel compounds and analogs which inhibit the serotonin N-acetyltransferase enzyme, and to processes for their preparation.

Inhibitors of sorotonin N-acetyltransferase

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Baltimore, MD, United States of America

Philip A Cole