Emerging Ubiquitin and Autophagy Targets


( 新泛素与自噬作用标的 )

Autophagy and the ubiquitin-proteasome system (UPS) are the two major pathways responsible for protein degradation and maintenance of cellular homeostasis. They consist of well-controlled, selective mechanisms for intracellular protein degradation and turnover. New understanding of the role and molecular mechanisms involved in the dysregulation of autophagy and ubiquitin pathways has revealed its underlying role in cancer, CNS, immunology and other diseases. However, the diversity of substrates and the multi-step processes involved, make it difficult to target these pathways for therapeutic intervention. In recent years, the development of high-quality chemical probes, small molecule modulators, assays and screening platforms have helped identify novel autophagy and ubiquitin targets for drug discovery. Cambridge Healthtech Institute’s conference on Emerging Ubiquitin and Autophagy Targets will bring together a diverse group of chemists and biologists to discuss the promise and challenges in this area of research. This conference will be followed by one that focuses exclusively on targeted protein degradation using proteolysis-targeting chimeric molecules (PROTACs) and other molecular entities for hijacking the ubiquitin system.

Choose 2 Short Courses and 2 Conferences/Training Seminars
September 16 Pre-Conference Short Course: SC6: Biochemistry and Pharmacology of the Ubiquitin-Proteasome System
September 17-18 Conference: Emerging Ubiquitin and Autophagy Targets
September 18 Dinner Short Course: SC9: Targeted Protein Degradation Using PROTACs, Molecular Glues and More
September 18-19 Conference: PROTACs and Targeted Protein Degradation

Final Agenda


1:00 pm Pre-Conference Short Course Registration
Click here for details on short courses offered.


7:00 am Registration Open and Morning Coffee

Probing PPI & Protein Degradation

8:00 Organizer's Welcome Remarks

8:05 Chairperson’s Opening Remarks

Matthew DeLisa, PhD, William L. Lewis Professor of Engineering, Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University

8:10 New Technologies to Discover E3 Ligase Inhibitors, Activators, Hijackers

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

Two major principles of targeting the ubiquitin system have emerged: direct targeting of the enzymes that control protein ubiquitination and hijacking E3 ligases to induce protein degradation. In this lecture, I will outline the discovery of novel probes UbFluor and cross-linking reagents to discover small molecule inhibitors/activators and hijackers for RBR/HECT E3 ligases. I will then show how UbFluor technology can be used to discover nanomolar inhibitors of HECT E3 ligases.

8:40 Drugging the Fbw7 E3 Ligase with a Combined Computational and Fragment-Based Approach

Galdeano_CarlosCarles Galdeano, PhD, Serra Hunter Professor, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona

We have developed a multidisciplinary computational and biophysical approach to identify ligands that target E3 ligases, and specifically the Fbw7 E3 ligase. Fbw7 is one of the most commonly deregulated UPS protein in human cancers, which targets some key human onco-proteins including cyclin-E, MYC, Notch and Junk. So far, no potent small molecule directly targeting the Fbw7 complex has been reported. Our approach has allowed us to identify ligands able to bind at the low micromolar level to the Fbw7 protein. Work is on-going to elucidate the binding mode and the potential MOA of these ligands.

9:10 ULK3 Kinase as a Key Regulator of Cancer Associated Fibroblast Conversion

Goruppi_SandroSandro Goruppi, PhD, Instructor in Dermatology, Harvard Medical School, Cutaneous Biology Research Center, Massachusetts General Hospital

The connection between pathways and the role of microenvironment metabolic alterations in cancer associated fibroblasts (CAFs) activation is unknown. CSL/RBPJ suppress gene expression program(s) leading to CAF activation. GLI signaling also contributes to CAF conversion. I will report on a degradative autophagy mechanism targeting CSL and leading to CAF activation. Then I will outline the identification and targeting of ULK3 kinase, which links CSL and GLI signaling and represent a tool for stroma-focused anti-cancer intervention.

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

10:25 Analysis of Mammalian ER-Associated Degradation Using Genome-Wide CRISPR Screens

Leto_DaraDara E. Leto, PhD, Basic Life Research Scientist, Departments of Biology, Genetics, Chemical and Systems Biology and Program in Chemistry, Engineering and Medicine for Human Health, Stanford University

Only a handful of ubiquitin-proteasome system (UPS) components have been linked to the recognition and degradation of specific protein quality control substrates. To identify genes required for the destruction of distinct clients of the ER-associated degradation (ERAD) system, we developed a screening approach that combines genome-wide CRISPR-Cas9-mediated gene deletions and a phenotypic selection based on protein turnover kinetics. Our findings show that forward genetic analysis can be used to discover new biochemical pathways in protein quality control.

10:55 Engineering Protein-Protein Interactions to Probe and Rewire Ubiquitin Signaling

Zhang_WeiWei Zhang, PhD, Assistant Professor, Molecular and Cellular Biology, University of Guelph

Advances of genomic technologies accelerated the identification of signal transduction cascades essential for initiation and progression of human diseases. In particular, protein-protein interactions in ubiquitin signaling are found to play critical roles in eliciting numerous mis-regulated biological functions. We employ structure-based combinatorial protein design and engineering strategies to develop potent and selective modulators to probe the ubiquitin signaling pathways with unprecedented precision for underlying molecular mechanisms and potential therapeutics.

11:25 Structures of the Substrate-Engaged Proteasome Reveal the Mechanism of Translocation and Activation

Hernandez_AndresAndres Hernandez de la Peña, PhD, Scientist I, Structural and Chemical Biology, Celgene

As the primary eukaryotic proteolytic machine, the 26S proteasome is responsible for ubiquitin-mediated degradation of misfolded, damaged, or obsolete proteins. We determined several structures of the proteasome as it actively translocated substrate. These structures reveal the mechano-chemical coupling of ATP hydrolysis to substrate translocation and gate opening. Additionally, these structures reveal a co-translocational deubiquitination mechanism that positions ubiquitin and the isopeptide scissile bond in the Rpn11 deubiquitinase.

11:55 Presentation to be Announced

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

Developing Small Molecule Ubiquitin-Mediated Degradation

1:50 Chairperson’s Remarks

Yue Xiong, PhD, William R. Kenan Professor of the Biochemistry and Biophysics, University of North Carolina; Co-Founder, Cullgen

1:55 SMARCA2/4 Degraders for Cancer Therapy

Ramachandra_MuraliMurali Ramachandra, PhD, CEO, Aurigene Discovery Technologies Limited

SMARCA2 and SMARCA4 are ATPases in the SWI/SNF complexes, which function in regulating transcription, DNA replication and repair. SMARCA4 is mutated in a number of cancers, which are dependent on functional SMARCA2. SMARCA4 is also highly expressed without mutation in certain other tumor types, where overexpression contributes to proliferation and survival. In view of these findings, our efforts in developing novel bi-functional molecules inducing proteasome-mediated degradation of SMARCA2/4 for the treatment of cancers will be presented.

2:25 Ubiquitin-Mediated Small Molecule Induced Target Elimination in Cancer

Yue Xiong, PhD, William R. Kenan Professor of the Biochemistry and Biophysics, University of North Carolina; Co-Founder, Cullgen

Development of small molecules to target ubiquitin-dependent degradation of disease-linked proteins represents a promising opportunity for the drug discovery. Multiple such small molecules have been developed based on different E3 ubiquitin ligases. I will discuss the catalytic mechanism, assembly and regulation of cullin-RING E3 ubiquitin ligases (CRLs). I will also present our efforts in developing novel degraders targeting different human cancer protein. Finally, I will share some thoughts on the development of novel E3 ligands.

2:55 Sponsored Presentation (Opportunity Available)

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


4:05 New Ubiquitin Ligases and Novel PROTAC Approaches

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

Ligases that reside primarily in the nucleus are not suited to cytosolic targets, for example, while membrane-associated ligases are required to target GPCRs and other membrane associated targets. Novel E3 ligases and ligands would thus expand the therapeutic potential of PROTACs and provide new IP. I will present data on PROTACs that hijack novel ubiquitin ligases to ubiquitylate targets affecting immune oncology and anti-inflammatory cascades. Degradative versus non-degradative ubiquitylation and relationships between the type of ubiquitylation and PROTAC-targeted function will be discussed.

4:35 Broad-Spectrum Proteome Editing with an Engineered Bacterial Ubiquitin Ligase Mimic

DeLisa_MatthewMatthew DeLisa, PhD, William L. Lewis Professor of Engineering, Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University

Ubiquibodies are comprised of a synthetic binding protein fused to an E3 ubiquitin ligase, thus enabling post-translational ubiquitination and degradation of a target protein independent of its function. Here, we have designed a panel of new ubiquibodies based on E3 ubiquitin ligase mimic from bacterial pathogens that enable selective and customizable removal of proteins of interest. Delivery of synthetic mRNA encoding ubiquibodies caused efficient target depletion in cultured mammalian cells as well as in transgenic mice. Overall, our results suggest that engineered ubiquibodies are a highly modular proteome editing technology with the potential for pharmacologically modulating disease-causing proteins.

5:05 Interactive Breakout Discussion Groups - View All Breakouts

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.

New Technologies and Assays to Study Protein Degraders

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

Carles Galdeano, PhD, Serra Hunter Professor, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, University of Barcelona

Yue Xiong, PhD, William R. Kenan Professor of the Biochemistry and Biophysics, University of North Carolina; Co-Founder, Cullgen

  • Biological insights into the ubiquitin-proteasome system pathway
  • Target validation approaches for novel proteostasis targets
  • Biochemical, biophysical and cellular-based approaches to monitor ternary complex formation
  • Approaches to identify novel E3 ligases and E3 ligase ligands

Novel Applications and Approaches for PROTAC-Based Protein Degradation

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

  • Current limitations of PROTAC approaches – application of cereblon, cIAP, VHL, HDM2 ligases as degrader molecules ligase
  • Big hurdles in therapeutic potential of PROTACs – toxicity for chronic diseases, oral bioavailability, IP issues 
  • Expanding therapeutic potential of PROTACs – developing novel ligases for membrane, cytosol, or nuclear targets
  • How to overcome the above hurdles and not to develop “Me Too” PROTACs

Challenges with Developed Targeted Protein Degrader Molecules

Moderators: Murali Ramachandra, PhD, CEO, Aurigene Discovery Technologies Limited

Upendra Dahal, PhD, Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.

  • Differential activity in cells and preclinical models
  • PK/PD relationships
  • Bell-shaped dose response
  • Achieving oral bioavailability
  • BBB permeability
  • CMC challenges

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

7:10 Close of Day


7:30 am Registration Open and Morning Coffee

Emerging Ubiquitin Targets & Modulators

8:00 Chairperson’s Remarks

Mary Matyskiela, PhD, Principal Scientist and Group Leader, Structural and Chemical Biology, Celgene

8:05 Potent Small Molecule Parkin Activators for Treating Neurodegenerative Diseases

Kumar_SureshSuresh Kumar, PhD, Senior Director R&D, Progenra, Inc.

Parkin, an ubiquitin E3 ligase, is a critical regulator of mitochondrial dynamics and a protector of neuronal health. Inactivating mutations in both Parkin and PINK1 are found in Parkinson’s disease patients. Using the UbiProTM HTS platform we have discovered novel small molecule Parkin activators. Parkin activators promote degradation of mitochondrial and cytosolic Parkin substrates in human neurons. Development of these Parkin activators offers potentially viable therapeutic options to treat Parkinson’s and other neurodegenerative diseases.

8:35 A Neurodevelopmental Disorder Caused by USP7 Haploinsufficiency

Potts_RyanRyan Potts, PhD, Associate Member, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital

USP7 is a prominent deubiquitinating enzyme that has a multitude of cellular functions. Most notably its role in regulation of p53 has garnered much attention. This has resulted in tremendous interest in development of USP7 inhibitors for cancer treatment. Here, I will discuss progress in understanding how mutation or deletion of a single copy of USP7 leads to a neurodevelopmental disorder. The implications of these findings in drug development will be discussed.

9:05 Solving a 60 Year Mystery: SALL4 Mediates Teratogenicity as a Thalidomide-dependent Substrate of Cereblon

Matyskiela_MaryMary Matyskiela, PhD, Principal Scientist and Group Leader, Structural and Chemical Biology, Celgene

Targeted protein degradation through small molecule modulation of cereblon offers vast potential for new therapeutics, but cereblon-binding molecules carry the safety risks of thalidomide, which caused an epidemic of severe birth defects in the 1950s. We identify SALL4 as a thalidomide-dependent cereblon substrate whose degradation phenocopies genetic embryopathies caused by SALL4 mutation. This work offers a path towards safer therapeutics through understanding the molecular basis of thalidomide-induced teratogenicity, and expands the scope of cereblon neosubstrates.

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

10:20 FEATURED PRESENTATION: Advancing Targeted Protein Degradation for CNS Proteinopathies

Haggarty_StephenStephen. J. Haggarty, PhD, Associate Professor, Department of Neurology, Harvard Medical School; Associate in Neuroscience and Director, Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital

Exploiting the control of protein proximity to catalyze targeted protein degradation provides a potentially powerful therapeutic strategy. Recent advances enabling the generation of patient-derived, ex vivo models of central nervous system (CNS) proteinopathies and the development of bifunctional molecules capable of selectively targeting pathological protein conformations now allow this strategy to be applied to the context of neurodegeneration. Here we will summarize recent findings focused on targeted degradation of tau, a protein implicated in multiple forms of dementia.

11:20 Enjoy Lunch on Your Own

11:20 Conference Registration for Programs 1B-7B

Click here for full abstracts.

12:20 pm Event Chairperson’s Opening Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute


12:30 Plenary Keynote Introduction

Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd

12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells

David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University



1:20 PROTACs: Past, Present, and Future

Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University



2:00 Close of Plenary Keynote Program

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

2:45 Close of Emerging Ubiquitin and Autophagy Targets Conference
Please click here to continue to the agenda for PROTACs and Targeted Protein Degradation

* 活动内容有可能不事先告知作更动及调整。

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