Targeting The Ubiquitin Pathway

 

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Drugs targeting the ubiquitin system are still relatively new; the first approval by the FDA happened in 2003. Ubiquitination (ligases) as well as deubiquitination (deubiquitylating enzymes (DUB’s) play key roles in cellular signal transduction pathways and offer numerous opportunities for therapeutic interventions for treating diseases such as cancer, inflammation and metabolic diseases. However, in order to bring more ubiquitin targeting drugs to the market, some challenges need to be addressed and will be discussed at this meeting.

MONDAY, OCTOBER 1

7:00 am Conference Registration and Morning Coffee


Ubiquitin Perspectives

8:30 Chairperson’s Opening Remarks

Andrei Gartel, Ph.D., Associate Professor, Medicine, University of Illinois

8:40 Roles of Ubiquitin and Ubiquitin-Like Proteins in Autophagy

Vladimir Kirkin, Ph.D., Senior Scientist, Merck-Serono; Research & Early Development, Oncology Platform, In Vivo Pharmacology, Merck KGaA

Autophagy can be a highly selective process, whereupon deleterious structures (protein aggregates, damaged mitochondria or microbes) are recognized, sequestered by the nascent autophagosome from the rest of the cytosol and delivered to the lysosome for degradation. Ubiquitination is a crucial modification responsible for labeling autophagic substrates and targeting autophagosome formation to a specific site in the cell. On the autophagosome's side, ubiquitin-like proteins LC3/GABARAP covalently attached to the vesicle, are equally important for the target-induced autophagosome formation. Selective autophagy receptors, such as p62/SQSTM1, by binding both ubiquitin and LC3/GABARAP, can provide the bridge between the ubiquitinated cargo and the autophagosome formation and thus represent a class of emerging drug targets relevant to infection diseases, neurodegeneration and cancer.

9:10 Ubl Peptidase in Human Protozoan Parasite Leishmania donovani as a Potential Drug Target

Sreenivas Gannavaram, Ph.D., Scientist, Division of Emerging and Transfusion Transmitted Diseases, OBRR/CBER/FDA

Ubl's regulate/modify the functions of a wide range of proteins. In our laboratory we have identified Ufm1 mediated protein conjugation to be essential for Leishmania amastigotes, the parasite stages found in human host. Therefore, proteases associated with Ufm1 conjugation activities can provide for potential new drug targets to combat human leishmaniasis because of lack of vaccines and increasing drug resistance to a few existing drugs against Leishmania. Results on the characterization of Ufm1 associated peptidase will be discussed.

9:40 Advancing Drug Discovery in the Ubiquitin Pathway

Ben Nicholson, Ph.D., Director, Biology, Progenra

Progenra and their partners have been working to address the challenges of identifying small molecule inhibitors of both deubiquitylating enzymes and E3 ligases by developing novel assay formats. Specifically, data will be presented highlighting Progenra’s novel deubiquitylating enzyme and E3 ligase assay formats. Furthermore, specific examples of Progenra’s diverse drug discovery projects will be presented, confirming Progenra’s ability to identify novel modulators of these highly relevant therapeutic pathways.

10:10 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing


Targeting the Proteasome System

10:40 Developing Allosteric Inhibitors Targeting the Proteasome Assemblies

Maria Gaczynska, Ph.D., Associate Professor, Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio

The proteasome, with its modular structure and multiple activities is a perfect target for allosteric drugs. They may affect single activities or their combination, and may interfere with stability of higher-order proteasome assemblies. In particular, the interface between the core and regulatory modules is rich in allosteric hot spots. The novel approach of targeting the interface with allosteric ligands exhibiting anti-cancer or anti-inflammatory properties will be presented and discussed.

EMD Millipore11:10 Degrading the Barriers to Drug Discovery in Ubiquitin E3 Ligase Pathways

Blaine N. Armbruster, Ph.D., Senior Manager, Discovery & Development Solutions, EMD Millipore Corporation 

11:40 Oncogenic Transcription Factor FOXM1 is a Major Target for Proteasome Inhibitors

Andrei Gartel, Ph.D., Associate Professor, Medicine, University of Illinois

The oncogenic transcription factor Forkhead Box M1 (FoxM1) is overexpressed in a majority of human cancers, while its expression is usually low in normal cells. All tested proteasome inhibitors target transcriptional activity and expression of FOXM1 in human cancer cells. Targeting of FOXM1 contributes to anticancer activity of proteasome inhibitors and may explain why they selectively kill cancer, but not normal cells. We propose a novel universal mechanism of FOXM1 suppression by proteasome inhibitors.

12:10 pm Enhancement of Proteasome Activity by a Small-Molecule Inhibitor of USP14

Daniel Finley, Ph.D., Professor, Cell Biology, Harvard Medical School

Usp14 inhibits proteasomes, by trimming the substrate’s ubiquitin chain, leading to substrate release from the proteasome before it can be degraded. A high-throughput screen identified a selective, small-molecule inhibitor (IU1) of Usp14. Treatment of cells with IU1 accelerated degradation of several proteins that have been implicated in neurodegenerative disease. Thus, proteasomes function under tonic inhibition by the deubiquitinating activity of Usp14.

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own


Ubiquitin Ligases

2:20 Chairperson’s Remarks

Domagoj Vucic, Ph.D., Senior Scientist, Early Discovery Biochemistry, Genentech, Inc.


2:25 FEATURED PRESENTATION

Ubiquitin and ER Quality Control

Hidde Ploegh, Ph.D., Member, Whitehead Institute for Biomedical Research, Professor of Biology, Massachusetts Institute of Technology

The role of the ubiquitin proteasome system in protein quality control is well established.  My lab has focused in particular, on aspects of quality control in the endoplasmic reticulum.  We have developed new models and tools (activity based probes) to identify enzymes that act in this pathway.


2:55 Targeting IAP Proteins: Ubiquitin Ligases at the Crossroads of Apoptosis, Inflammation and Cancer

Domagoj Vucic, Ph.D., Senior Scientist, Early Discovery Biochemistry, Genentech, Inc.

Inhibitor of apoptosis (IAP) protein family members block cell death in response to diverse stimuli and are expressed at elevated levels in many human cancers. We have designed small-molecule IAP antagonists that bind to IAP proteins resulting in a dramatic induction of c IAP auto-ubiquitination and rapid proteasomal degradation as well as inhibition of tumor growth in vivo. Understanding the significance of IAP E3 ligase activity is important for the design of novel therapeutics for the treatment of cancers.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 Identification of E3 Ubiquitin Ligase Substrates through Quantitative Proteomics

John Doedens, Ph.D., Scientist, Resolve Therapeutics

Identification of substrates for the diverse repertoire of E3 ubiquitin ligases encoded in the human genome remains a significant challenge for the field. We have applied protein-level and peptide level enrichment strategies combined with siRNA technology, SILAC, and quantitative mass spectrometry to identify substrates of the E3 ligase HRD1, an E3 proposed to function in the pathogenesis of rheumatoid arthritis. Validation of these methods and the identified substrates will be discussed.

4:35 Diverse Routes to the Proteasome: Role of SUMO-Specific Ubiquitin Ligases

Juergen Dohmen, Ph.D., Professor, Institute for Genetics, University of Cologne

The 26S proteasome of eukaryotic cells mediates the degradation of a diverse array of proteins. In most cases, degradation is promoted by poly-ubiquitylation of the substrate proteins. In other cases, however, proteins are degraded without prior modification. Ubiquitin-dependent degradation is moreover involved in the control of proteins that carry other ubiquitin-related modifiers such as SUMO. This process involves the activity of specialized ubiquitin ligases that recognize and ubiquitylate poly-sumoylated proteins, and thereby mediate their degradation by the proteasome. Recognition and targeting of sumoylated proteins by these ligases can be inhibited by competition with polypeptides bearing SUMO interaction motifs (SIMs). 

5:05 Interactive Breakout Discussion Groups

Challenges of Identifying E3 Ligases

Moderator: Blaine N. Armbruster, Ph.D., Senior Manager, Discovery & Development Solutions, EMD Millipore Corporation

Progress in Developing Therapeutics

Moderator: Philippe Nakache, Ph.D., Head, Chemistry, Proteologics

Allosteric Inhibitors – What is the Advantage?

Moderator: Maria Gaczynska, Ph.D., Associate Professor, Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio

  • "Allosteric inhibitor is a kind of poor inhibitor which never totally abolishes the enzyme's activity." True or False?
  • "Pharma industry is not interested in allosteric inhibitors." True or False?
  • Allosteric inhibitors of the proteasome as drugs: single-agent or in synergy with competitive inhibitors?
  • Small-molecule allosteric activators of the proteasome: any use of them? 
  • Non-proteasome targets for allosteric regulators in the ubiquitin pathway
 


 

6:15 – 7:30 Welcoming Reception in the Exhibit Hall with Poster Viewing

 

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