Targeting the Ubiquitin Proteasome System

Cambridge Healthtech Institute 第5回
脱ユビキチン化酵素 (DUB) とE3リガーゼの標的化によるタンパク質恒常性の調整

第15回Discovery on Targetの一翼を担うイベント

ユビキチンプロテアソーム系 (UPS) の標的化をテーマにしたこのプログラムでは、急速に拡大しつつあるこの分野で創薬に携わっている主要な研究者が専門分野の垣根を越えて集まります。

Final Agenda


· September 25 Symposium: Targeting Autophagy

· September 25 Short Course: Covalent Fragments: Applications in Target-Based and Phenotypic Screens

· September 26-27 Conference: Targeting the Ubiquitin Proteasome System

· September 27-28 Conference: Kinase Inhibitor Discovery

· September 27 Short Course: Introduction to Targeted Covalent Inhibitors

· September 28-29 Symposium: CNS and Neurodegenerative Targets

Tuesday, September 26

7:00 am Registration Open and Morning Coffee


8:00 Welcome Remarks

Kip Harry, Senior Conference Director, Cambridge Healthtech Institute

8:05 Chairperson's Opening Remarks

Ingrid E. Wertz, M.D., Ph.D., Senior Scientist, Discovery Oncology and Early Discovery Biochemistry, Genentech, Inc.

8:10 FEATURED PRESENTATION: Targeted Protein Degradation by Small Molecules

Alessio Ciulli, Ph.D., Associate Professor, Chemical & Structural Biology, School of Life Sciences, University of Dundee

The application of small molecules to induce selected protein degradation is emerging as a transformative new modality of chemical intervention in drug discovery. We have previously shown that linking a VHL ligand that we had discovered with a pan-BET inhibitor creates highly selective PROTAC molecule MZ1. MZ1 triggers preferential intracellular degradation of Brd4, leaving the homologous BET members untouched, and exhibits greater anti-proliferative activity in leukemia cell lines than pan-BET inhibition.

8:40 Target Protein Degradation for New Therapeutics

Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor, Medicine; Professor, Medicine, Pharmacology and Medicinal Chemistry; Director, Center for Therapeutics Innovation, University of Michigan

Recently, a new small-molecule approach has been employed to target degradation of BET proteins through the design of bifunctional, Proteolysis-Targeting Chimera (PROTAC) molecules. Based upon our new classes of highly potent small-molecule BET inhibitors, we have designed and optimized highly potent and efficacious small-molecule degraders of BET proteins. We have performed critical and extensive evaluation of our BET degraders for their therapeutic potential and mechanism of action in models of acute leukemia and solid tumors.

9:10 Targeted Protein Degradation via Redirecting the Action of CRL4 E3 Ligases

Brian Cathers, Ph.D., Executive Director, Co-Leader & Head, Drug Discovery, Protein Homeostasis Thematic Center of Excellence, Celgene

Distinct cereblon binding molecules evoke different phenotypic responses yet bind the same target. Solution of the ligand bound CRBN complex provides a rationale for distinguishing "gain of function" targeting of key substrates including the transcription factors Aiolos and Ikaros, the protein kinase CK1α, or the translation termination factor GSPT1. Is it possible to harness the action of a single E3 ligase and direct its actions toward new and different substrates? Are other ligases able to be co-opted in a similar fashion?

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:25 Targeted Protein Degradation

Andrew Phillips, Ph.D., CSO, C4 Therapeutics

10:55 Targeted Protein Degradation by PROTACs

Yimin Qian, Ph.D., Senior Director, Medicinal Chemistry, Arvinas

We highlight the advantages of protein degradation using PROTACs, and provide specific examples where degradation offers therapeutic benefit over classical enzyme inhibition. PROTACs can degrade proteins regardless of their function. This includes the currently "undruggable" proteome, which comprises approximately 85% of all human proteins. Other beneficial aspects of protein degradation include the ability to target overexpressed and mutated proteins, as well as the potential to demonstrate prolonged pharmacodynamics effect beyond drug exposure.

11:25 KEYNOTE PRESENTATION: Covalent Inhibitors and Degraders of Challenging Targets in Cancer

Nathanael Gray, Ph.D., Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; Professor, Cancer Biology, Dana-Farber Cancer Institute

This presentation will discuss new pharmacological strategies towards targeting kinases and other targets. Small molecules capable of inducing protein degradation through the recruitment of E3 ligases will be discussed with a focus on kinases. A general approach for identifying the most easily degradable kinase targets will be presented. Chemical design principles for developing degraders will be discussed. New approaches for developing covalent kinase inhibitors will also be discussed.

11:55 Sponsored Presentation (Opportunity Available)

12:25 pm Session Break

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing


1:50 Chairperson's Remarks

Gerald Gavory, Ph.D., Head, Biology, Alma Discovery

1:55 Ubiquitin -Omics for Target Discovery in Human Disease

Benedikt Kessler, Ph.D., Professor of Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford

Mass spectrometry can now cover the proteome in the ten thousand range, and ubiquitylation can be profiled in the thousands, covering enough depth to interrogate DUB and E3 ligase substrates. The ubiquitin-specific protease USP7 was suggested as a potential drug target for Multiple Myeloma, where the treatment with small molecule USP7 inhibitors overcomes resistance to clinical proteasome inhibitors. We have utilized activity-based profiling, chemical proteomics and structural analysis to determine the potency of novel deubiquitylating enzyme inhibitors.

2:25 Developing a Quantitative Profiling Platform to Evaluate Endogenous Deubiquitinase Activity

Ingrid E. Wertz, M.D., Ph.D., Senior Scientist, Discovery Oncology and Early Discovery Biochemistry, Genentech, Inc.

Here we describe the development of an analysis platform that combines DUB ABPs with chemical multiplexing, targeted mass spectrometry, novel internal reaction standards, and a customized statistical analysis program. Our strategy allows us to quantitate changes in DUB activity across a theoretically unlimited number of samples in a high-throughput manner. We illustrate the efficacy of this technology by evaluating the activity of disease-relevant DUBs, in analyzing DUB inhibitor selectivity, and in evaluating how compounds impact DUB activity.

2:55 Sponsored Presentation (Opportunity Available)

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:05 Small Molecule Ubiquitin Protease (USP7) Inhibitors with Immune Cell Based Anti-Tumor Activity Superior to that of Biologicals

Tauseef R. Butt, Ph.D., President and CEO, Progenra, Inc.

In immune competent animal models, USP7 inhibitors are potent anti-tumor agents, not only blocking tumor growth but also eliminating tumor metastasis. These results constitute the first example of a small molecule single agent that works by targeting both the tumor itself and the host immune system and also by eliminating tumor metastasis. In animal models, the USP7 inhibitor demonstrates activity that is superior to that of PD1 and CTLA4 antibodies.

4:35 Development and Further Exploitation of UbiPlex - A Proprietary Drug Discovery Platform for DUBs

Gerald Gavory, Ph.D., Head, Biology, Alma Discovery

We will describe our latest efforts and developments in targeting members of the DUB family using USp7, USP19 and new DUBs as case examples. UbiPlex delivered the first genuine and highly potent and selective inhibitors of multiple DUBs hence demonstrating the druggability and tractability of this so far refractory target class.

5:05 Interactive Breakout Discussion Groups

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

6:05 Welcome Reception in the Exhibit Hall (Sponsorship Opportunity Available)

7:10 Close of Day

Wednesday, September 27

7:30 am Registration Open and Morning Coffee


8:00 Chairperson's Remarks

Benedikt Kessler, Ph.D., Professor, Biochemistry and Life Science Mass Spectrometry, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford

8:05 Discovery of Novel Protein Homeostasis Inhibitors Utilizing FORMA's Drug Discovery Engine

Stephanos Ioannidis, Ph.D., Head, Early Portfolio, FORMA Therapeutics

Protein homeostasis is important in oncology, neurodegenerative and other medical disorders involving a network of pathways controlling the biogenesis, folding, transport and degradation of proteins. Using FORMA's innovative chemical libraries approach has led to the discovery of novel protein homeostasis inhibitors which allowed the understanding of pathways and targets associated with excessive protein degradation. The discovery of novel protein homeostasis inhibitors provides the potential for widespread clinical applications.

8:35 SUMOylation in Cancer Biology

Lawrence Dick, Ph.D., Director, Biochemistry, Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co.

SUMOylation has been implicated in many cellular processes that are important for cancer cell survival, including cell cycle, chromosome structure and segregation, nuclear and subnuclear organization, transcription and DNA damage repair. However, a potent and selective inhibitor to target the SUMO pathway has been lacking. The SUMO-activating enzyme (SAE) is an essential enzyme in the pathway that initiates the SUMOylation process. Here we report the identification of the first mechanism-based SAE inhibitor with nanomolar potency in cellular assays.

9:05 Sponsored Presentation (Opportunity Available)

9:35 Coffee Break in the Exhibit Hall with Poster Viewing


10:20 HECT E3 and RBR E3 Ligases as Drug Targets to Treat Cancer and Neurodegenerative Diseases: Basic Science and New Screening Technologies

Alexander Statsyuk, Ph.D., Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

E3 ligases (>600 known) are the key mediators of protein degradation pathways, and E3 ligase inhibitors or activators are promising drug leads. In addition, E3 ligases can be executors that mediate the degradation of PROTAC targets. In this presentation, we specifically discuss emerging biochemical mechanisms and biological roles of HECT and RBR E3 ligases, their therapeutic potential to treat cancers and neurodegenerative diseases, and current screening technologies to discover initial drug leads for this class of drug targets.

10:50 Inhibition of an E2/E3 Protein-Protein Interaction as a Novel Strategy to Interfere with E3 Ligase Activity

Kamyar Hadian, Ph.D., Principal Investigator & Head, Assay Development and Screening Platform, HelmholtzZentrum Munchen

This lecture will give insights into the discovery of a novel E2/E3 protein-protein interaction small molecule inhibitor that we were able to validate and characterize in a variety of biochemical as well as cell-based assays including primary mouse and human cells. More importantly, we can show that this first-in-class inhibitor is effective in preclinical autoimmune mouse models for psoriasis as well as rheumatoid arthritis.

11:20 Enjoy Lunch on Your Own

12:20 pm Plenary Keynote Program

(click here for details)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

2:45 Close of Conference

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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