Harvard College

Taiho Pharmaceutical Company Limited

Randall W King

Daniel J Finley

Byung-Hoon Lee

Marc W Kirschner

Timothy Gahman

Min Jae Lee

Xing Zeng

Timothy C Gahman

Matthew D Shair

Shantanu K Gaur

Henry Efrem Pelish

Alexander Arefolov

Kevin D Lustig

Maria Paola Castaldi

Jennifer E Ring

Stefan Jentsch

John W Hanna

P Todd Stukenberg

P Renee Yew

Katharine L Sackton

Nathaniel A Hathaway

Jan-Michael Peters

Eun Sun Park

Astrid S Clarke

Grace L Williams

Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.

Compositions and methods for enhancing proteasome activity

Tricyclic proteasome activity enhancing compounds

The disclosure provides compositions and methods for treating cell cycle disorders. Compositions of the disclosure include proTAME, a prodrug analog of TAME and apcin, the combination of which inhibits an activity or function of the anaphase promoting complex (APC) by a synergistic mechanism.

Cell permeable inhibitors of anaphase promoting complex

The invention provides an anti-proliferative composition comprising a non-peptide analog of the C-terminal isoleucine-arginine (IR) tail motif of an activator of an anaphase promoting complex (APC). The invention further provides methods of inhibiting the ubiquitination activity of the APC by administering compositions of the invention.

Inhibitors of anaphase promoting complex activity

This invention relates to methods and compositions for enhancing proteasome activity in a cell. The methods and compositions for enhancing the activity of the proteasome in cells modulate the activity of Ubp6 (yeast) or Usp14 (human), an endogenous inhibitor of the proteasome. The methods and compositions partially or completely reduce the inhibitory activity of Usp14 on a proteasome, thereby specifically enhancing the protein-degradation activity of the proteasome. The invention also provides methods of screening to identify inhibitors of Ubp6, Usp14, and/or both Ubp6 and Usp14.

Methods and compositions for enhancing proteasome activity

The present invention provides methods of identifying an agent that modulates PRPK, TPRKB, OSGEP, LAGE3 and its homologs, PRPK/TPRKB complex, and/or KEOPS complex. The present invention also provides compositions of such agents and methods of treating a disease, disorder, or condition associated with PRPK, TPRKB, OSGEP, LAGE3 and its homologs family (CT antigens), PRPK/TPRKB complex, and/or KEOPS complex using such an agent or composition.

PRPK-TPRKB modulators and uses thereof

Disclosed herein are novel ubiquitin-conjugating enzymes and methods for using same. More specifically, disclosed are nucleic acid sequences encoding the UBC9 protease.

Ubiquitin conjugating enzymes

The present invention provides a systematic and practical approach for the identification of candidate agents able to inhibit ubiquitin-mediated degradation of a cell-cycle regulatory protein, such as cyclins. One aspect of the present invention relates to a method for identifying an inhibitor of ubiquitin-mediated proteolysis of a cell-cycle regulatory protein by (i) providing a ubiquitin-conjugating system that includes the regulatory protein and ubiquitin under conditions which promote the ubiquitination of the target protein, and (ii) measuring the level of ubiquitination of the subject protein brought about by the system in the presence and absence of a candidate agent. A decrease in the level of ubiquitin conjugation is indicative of an inhibitory activity for the candidate agent. The level of ubiquitination of the regulatory protein can be measured by determining the actual concentration of protein:ubiquitin conjugates formed; or inferred by detecting some other quality of the subject protein affected by ubiquitination, including the proteolytic degradation of the protein.

Assay and reagents for detecting inhibitors of ubiquitin-dependent

The present invention provides improvements in the expression cloning method for isolating novel cDNA clones. In particular, in the expression cloning method comprising the steps of preparing a cDNA library from a cell that expresses a desired protein; inserting the cDNA library into an expression vector; inserting the cDNA library into bacterial cells and culturing the bacterial cells to produce individual bacterial colonies; collecting pools of a predetermined number of individual bacterial colonies; isolating the cDNAs contained in the pools; expressing proteins encoded by the cDNAs; and detecting the desired protein, positive clones may be efficiently and cost-effectively obtained by collecting pools of about 100 individual bacterial colonies and expressing proteins encoded by the cDNAs in the pools in vitro.

Method of expression cloning

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Brookline, MA, United States of America

Randall W King