UBQ

Cambridge Healthtech Institute 第1届

Ubiquitin Proteasome System Inhibitors

( 泛素-蛋白酶体系统抑制剂 )

以DUB酵素及连接酶为标的的小分子药物之发现与开发

2018年4月4-5日 | | Hilton Bayfront | 加州圣地牙哥

 

泛素-蛋白酶体系统(UPS)是为了严格控管细胞内蛋白质分解与代谢流通的必要调控机制。对于UPS成分在疾病中所扮演的角色及分子机制的进一步了解,以及高品质化学工具和创新抑制剂的开发,UPS从遥不可及的标的,变成发展创新药物时最为茁壮且令人兴奋的舞台之一。最近数年间,制造了很有可能开始进行临床开发试验的DUB抑制剂,以及干扰E3连接酶蛋白质间交互作用、取代UPS降解目标蛋白质、以免疫蛋白质体为标的的抑制剂及创新方法。

本研讨会以泛素-蛋白酶体系统抑制剂为主题,将会邀集跨领域的专家团队,一同推动UPS药物开发的快速开发领域。


Final Agenda

Wednesday, April 4

12:30 pm Registration

12:45 Dessert Break in the Exhibit Hall with Poster Viewing

HIJACKING THE UPS FOR TARGETED PROTEIN DEGRADATION

1:30 Welcome Remarks

Kip Harry, Senior Director, Conferences, Cambridge Healthtech Institute

1:35 Chairperson's Opening Remarks

Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

1:40 Targeted Protein Degradation via Redirecting the Action of CRL4 E3 Ligases

Brian_CathersBrian Cathers, PhD, 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?

2:10 PROTACs: The Chemical Equivalent of CRISPR

Dan_BondesonDan Bondeson, Research Scientist, Crews Lab, Yale University

Induced protein degradation offers several advantages over traditional inhibition strategies and has emerged recently as a potential therapeutic option. For the past 16 years, we have helped develop this fast growing field, shepherding our initial chemical biology concept into a drug development strategy that is on the verge of clinical validation. PROTACs with high target selectivity, potency, and oral bioavailability will be discussed as well as a system to address the 'PROTACability' of particular E3 ligases.

2:40 Covalent Inhibitors and Degraders of Challenging Targets in Cancer

Dennis Dobrovolsky, Research Scientist, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

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.

3:10 Sponsored Presentation (Opportunity Available)

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Targeted Protein Degradation by Small Molecules

Alessio_CiulliAlessio Ciulli, PhD, 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.

5:00 Target Protein Degradation for New Therapeutics

Shaomeng_WangShaomeng Wang, PhD, 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.

5:30 Breakout Discussions

6:15 End of Day

6:30 Dinner Short Courses*

*Separate registration required.

Thursday, April 5

8:00 am Breakfast Presentation: Improvements in NMR Approaches to Fragment Based Screening

Donna Baldisseri, Senior Applications Scientist, Bruker BioSpin

FBDD is a powerful search engine for identification of fragments that bind to disease relevant target proteins ultimately leading to drug candidates. NMR-based FBDD screening requires compound library validation, preparation of hundreds of samples per campaign, automated acquisition, processing of thousands of spectra, and their analysis for binding assessment. Here is described the streamlined solutions offered by Bruker, automating this pipeline to improve the speed and productiveness of FBDD screening for the pharmaceutical industry.

8:45 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

8:50 Sponsored Plenary Keynote Introduction (Opportunity Available)


8:55 PLENARY KEYNOTE: Activity-Based Proteomics: Protein and Ligand Discovery on a Global Scale

Benjamin F. Cravatt, PhD, Professor and Co-Chair, Department of Molecular Medicine, The Scripps Research Institute

To address uncharacterized proteins, we have introduced chemical proteomic technologies that globally profile the functional state of proteins in native biological systems. Among these methods is activity-based protein profiling (ABPP), which utilizes chemical probes to map activity states of large numbers of proteins in parallel. I will discuss the application of ABPP to discover and functionally annotate proteins in mammalian physiology and disease, and the generation and implementation of advanced ABPP platforms for proteome-wide ligand discovery.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

DESIGN AND DEVELOPMENT OF NOVEL DEUBIQUITINASE (DUB) INHIBITORS

10:40 Chairperson's Remarks

Tauseef R. Butt, PhD, President and CEO, Progenra, Inc.

10:45 Small Molecule Ubiquitin Protease (USP7) Inhibitors with Immune Cell-Based Anti-Tumor Activity Superior to That of Biologicals

Tauseef_ButtTauseef R. Butt, PhD, 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.

11:15 Developing a Quantitative Profiling Platform to Evaluate Endogenous Deubiquitinase Activity

Willem den Besten, PhD, Senior Scientific Researcher, Genentech

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.

11:45 Sponsored Presentation (Opportunity Available)

12:00 pm Mining the Deubiquitinase Family for Novel Drugs Utilizing FORMA's Drug Discovery Engine

Stephanos_IoannidisStephanos Ioannidis, PhD, Head, Early Portfolio, FORMA Therapeutics

The deubiquitinating enzymes (DUBs), by their reversal of the ubiquitination/polyubiquitination process, are key enzymes regulating protein homeostasis. As such, modulators of DUB function have the potential to be important therapeutics in oncology, immunology, neurodegenerative and other medical disorders involving pathological or dysregulated proteins. FORMA Therapeutics deploys multiple drug discovery screening platforms to explore broad target families on scale. Panels of functional cellular and enzymatic assays, including related target family selectivity screens, were established to mine the DUBome for novel chemical matter.

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Dessert Break in the Exhibit Hall with Poster Awards

INSIGHTS INTO DEUBIQUITINASE ENZYMES AND INHIBITORS

2:15 Chairperson's Remarks

Zhihao Zhuang, PhD, Associate Professor, Department of Chemistry & Biochemistry, University of Delaware

2:20 Investigating Deubiquitination with Small Molecule and Ubiquitin-Based Probes

Zhihao_ZhuangZhihao Zhuang, PhD, Associate Professor, Department of Chemistry & Biochemistry, University of Delaware

Deubiquitinases (DUBs) play essential roles in a number of cellular processes and are implicated in many human diseases. In cells, individual DUBs are linked to specific cellular pathways, making them attractive targets for small molecule modulation. DUBs are also known to possess different types of ubiquitin chain linkage specificities. Understanding the DUB chain linkage specificity requires new probes to be developed. The probes can also be used to understand the different modes of ubiquitin chain binding and cleavage by DUBs.

2:50 USP7-Specific Inhibitors Target and Modify the Enzyme's Active Site via Distinct Chemical Mechanisms

Irina_BezsonovaIrina Bezsonova, PhD, Assistant Professor, Department of Molecular Biology and Biophysics, University of Connecticut

USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique among USPs in that its active site is catalytically incompetent, and is postulated to rearrange into a productive conformation only upon binding to ubiquitin.

3:20 Evaluation and Characterization of Small Molecule Inhibitors of Deubiquitinating Enzyme USP14 as Potential Anti-Cancer Agents

Stina _LundgrenStina Lundgren, PhD, Senior Research Scientist, Medivir AB


3:50 Refreshment Break

TARGETING THE PPIs OF E3 LIGASES

4:20 HECT E3 and RBR E3 Ligases as Drug Targets to Treat Cancer and Neurodegenerative Diseases: Basic Science and New Screening Technologies

Alexander_StatsyukAlexander Statsyuk, PhD, 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.

4:50 Novel Spiro[3H-indole-3,2´-pyrrolidin]-2(1H)-one Compounds as Potent, Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction

Andreas_GollnerAndreas Gollner, PhD, Laboratory Head, Medicinal Chemistry, Boehringer Ingelheim

Novel, chemically stable spiro[3H-indole-3,2´-pyrrolidin]-2(1H)-one compounds that are not prone to epimerization as observed for other spiro-oxindole MDM2-p53 inhibitors are presented. Structure-based optimization inspired by natural product architectures led to complex-fused ring systems ideally suited to interrupt the MDM2-p53 protein-protein interaction. The compounds are highly selective and show excellent in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for BI-0252.

5:20 Cep78, a Novel Inhibitor of the HECT E3 Ubiquitin Ligase EDD-DYRK2-DDB1DCAF1

William_TsangWilliam Tsang, PhD, Research Unit Director, Cell Division and Centrosome Biology, Montreal Clinical Research Institute

EDD-DYRK2-DDB1DCAF1 is a multi-subunit HECT E3 ubiquitin ligase whose physiological functions are not fully understood. We found that EDD-DYRK2-DDB1DCAF1 is present at the centrosome, an organelle crucial for cell division, and that its enzymatic activity is regulated by a novel centrosomal protein called Cep78 in human cells. By using a combination of biochemistry, molecular biology, and cell biology, we dissected the mechanism by which EDD-DYRK2-DDB1DCAF1 is inhibited by Cep78.

5:50 End of Conference

* 活动内容有可能不事先告知作更动及调整。