Cambridge Healthtech Institute’s Inaugural
Expanding Chemical & Druggable Space
Macrocyclics & Encoded Libraries, FBDD & Lead Generation, PROTACs
June 2-4, 2020
Progress of the past decade in encoded libraries and macrocyclic peptide synthesis are enabling new types of drug-like molecules to be created and rapidly screened, which is widening the ‘base’ from which successful drugs can be found. Moreover,
the types of intracellular targets these newer chemical entities can act upon is also expanding. Disease-relevant protein-protein interactions (PPIs) and larger molecular complexes can be disrupted by these larger, yet cell-penetrable drug-like compounds.
Fragment-based drug discovery (FBDD) and other biophysical screening approaches have also provided drug leads against such non-traditional, non-enzymatic drug targets. And now one of the latest innovations in drug discovery, PROTACs, special compounds
designed against any part of the target so that upon binding of the PROTACs the target is destroyed, is expanding therapeutic possibilities even more. But how good are all these new approaches? Is theory meeting practice? Join fellow discovery chemistry
and biology colleagues to hear case studies, discuss challenges, and share refinements that remain in the newest approaches for generating tomorrow’s orally-bioavailable medicines.
Final Agenda
Day 1 | Day 2 | Day 3 |
Download Brochure
SC5: Chemoproteomics Enabling Drug Discovery - Detailed Agenda
*Separate registration required.
Tuesday, June 2
Day 1 focuses on progress in macrocyclic peptide synthesis and applications of encoded libraries, two approaches that are widening the “base” from which successful drugs can be found.
10:00 am Main Conference Registration Open
11:15 Chairperson’s Remarks
Tomi Sawyer, PhD, President, Maestro Therapeutics
11:25 Development of Macrocyclic Peptides for Intracellular Targets
David Tellers, PhD, Principal Scientist, Discovery Chemistry, Merck Research Labs
Modulating intracellular protein-protein interactions (PPI) remains a compelling therapeutic opportunity. Peptides bridge the gap between small molecules and antibodies in terms of size and physical properties. As such, peptides potentially
have the right balance between target affinity and permeability to potentially address these challenges. This talk will focus on our efforts to develop macrocyclic peptides inhibitors of intracellular PPIs.
11:55 Passively Permeable Macrocycles: Inspiration from Nature and the Translation to the Bench
Cameron Pye, PhD, CEO and Co-Founder, Unnatural Products
We’ve been using passively permeable macrocycles found in nature as therapeutics for decades. However, designing this property into synthetic cyclic peptides has proved to be challenging despite the myriad of screening and selection platforms available.
This talk will explore how we leverage our platform to turn impermeable binders into passively permeable leads.
12:25 pm Engineering Cell-Permeable Proteins as Intracellular Biologics
Dehua Pei, PhD, Professor of Chemistry and Biochemistry, The Ohio State University
Current biologic drugs work almost exclusively against extracellular targets, because they cannot cross the cell membrane. We show that proteins (e.g., enzymes and nanobodies) can be rendered cell-permeable by genetically grafting short “cyclic”
cell-penetrating motifs into their surface loops. The engineered proteins are proteolytically stable and biologically active in cellular assays.
12:55 Transition to Lunch
1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:30 Session Break
2:00 Chairperson’s Remarks
Thomas Kodadek, PhD, Professor of Chemistry, The Scripps Research Institute; Co-Founder, Deluge Biotechnologies
2:05 Towards Macrocyclic Peptide Therapeutics using mRNA Encoded Libraries
Wayne Fairbrother, PhD, Director and Senior Staff Scientist, Early Discovery Biochemistry, Genentech
Development of small molecules modulating protein-protein interactions can be difficult due to large and shallow interaction interfaces. Antibodies are ideal for targeting PPIs, but they lack cell-permeability. Macrocycles occupy an intermediate
space between small molecules and antibodies, having sufficient size and functionality to interact specifically and with high affinity with PPI surfaces. Accordingly, mRNA display is a highly valuable technology to identify and optimize peptide-based
macrocycles.
2:35 Development of Scaffold-Diverse, Stereochemically-Rich DNA-Encoded Libraries and Their Application to Targeting the “Undruggable” Proteome
Thomas Kodadek, PhD, Professor of Chemistry, The Scripps Research Institute; Co-Founder, Deluge Biotechnologies
DNA-encoded libraries (DELs) are increasingly popular as a source of protein ligands. An important issue moving forward is to develop more structurally diverse and stereochemically complex DELs, particularly with respect to “largish” molecules
such as non-peptidic macrocycles that may be suitable for targeting difficult to drug proteins such as transcription factors. Recent efforts along these lines will be described.
3:05 Applications of ELT outside Therapeutic Lead Discovery
Christopher Arico-Muendel, PhD, Manager, Platform Capabilities, Encoded Library Technologies, R&D Platform Technology & Science, GlaxoSmithKline Discovery
Most applications of DEL seek stand-alone small molecule ligands to biological targets. However, the attached DNA tag identifies a site for linkage of additional moieties to create bispecific drugs, tool compounds, and affinity reagents. This presentation
describes the discovery of a novel, highly potent, specific binder to human serum albumin. Utility of the ligand for therapeutic half-life extension and for affinity purification of albumin containing therapeutics will be discussed.
3:35 Sponsored Presentation (Opportunity Available)
4:05 Networking Refreshment Break and Transition to Keynote
4:25 - 6:05 Driving Entrepreneurial Innovation to Accelerate Therapeutic Discoveries
The life sciences community has an unprecedented scientific arsenal to discovery, develop and implement treatments, cures and preventions that enhance human healthcare.
Moderator: Nadeem Sarwar, President, Eisai Center for Genetics Guided Dementia Discovery (G2D2), Eisai Inc.
Panelists: Anthony Philippakis, Chief Data Officer, Broad Institute; Venture Partner, GV
Barbara Sosnowski, Vice President and Global Head, Emerging Science & Innovation Leads, WWRDM, Pfizer
John Hallinan, Chief Business Officer, Massachusetts Biotechnology Council
6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:10 Close of Day
Day 1 | Day 2 | Day 3 |
Download Brochure
Wednesday, June 3
Day 2 focuses on applications of fragment-based drug design (FBDD) and associated biophysical techniques that are providing drug leads against more difficult targets. Now part of most drug discovery efforts, FBDD is a method for finding new drug leads
by screening libraries of low molecular weight fragments of drug-like organic compounds. Fragment-based libraries are especially suited for screening against newer types of drug targetssuch as intracellular protein-protein interactions (PPIs).
7:30 am Registration Open and Morning Coffee
8:10 Chairperson’s Remarks
Scott Cowen, PhD, Independent Medicinal Chemistry Consultant
8:15 Optimizing a Fragment Hit into Undruggable Space: A Case Study
Justin Dietrich, PhD, Senior Scientist III, Fragment Based Drug Discovery, AbbVie
We present a story on going from a small molecule fragment to an oral drug candidate with in vivo efficacy for a PPI program. For that story, we optimized a fragment into undruggable space to learn about the protein target
and then used that information and tools generated along the way to guide a second fragment program that focused on efficiency and maintaining drug-like properties for the final drug candidate.
8:45 From Fragment to Clinical Candidate: The Role of Biophysical Methods in Protein-Protein Interaction (PPI) Inhibitor Development
Chiara Valenzano, PhD, Senior Research Associate, Molecular Sciences Group, Astex Pharmaceuticals
This talk will offer the opportunity to discuss the impact that biophysical methods can have at different stages of the drug discovery process. By presenting case studies taken from the Astex pipeline, the advantages and limitations of applying biophysical
techniques such as NMR, SPR and X-ray crystallography to fragment-based drug discovery will be discussed.
9:15 The Application of Fragment Methods to Identify Allosteric Compounds
Ian Storer, PhD, Director of Chemistry, Head of FBLD, Astra Zeneca
A presentation covering examples of both structural (X-ray) and biophysical fragment screening to identify allosteric binders, providing examples from several AstraZeneca projects to illustrate the screening strategy and chemical optimisation from hits
to leads.
9:45 Sponsored Presentation (Opportunity Available)
10:15 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 SAR by 19F NMR: Using Protein-Observed Fluorine NMR for Targeting Protein Complexes
William Pomerantz, PhD, Professor, Chemistry, University of Minnesota
Inspired by the protein-observed NMR approach using 1H-15N-HSQC NMR, we have applied a complementary protein-observed 19F NMR (PrOF NMR) approach using 19F-labeled side-chains that are enriched at protein-protein interaction interfaces.
This talk will describe several case studies where PrOF NMR has been applied for fragment screening, ligand deconstruction, and screening of protein mixtures. Several new inhibitors of epigenetic complexes will also be highlighted.
11:30 CryoEM for Drug Discovery
Seungil Han, PhD, Cryo-EM Lab Head, Structural & Molecular Sciences, Pfizer Global R&D
This talk will describe applications of cryo-EM to investigations of solute carrier transporter proteins to enable drug discovery. The prospects of studying large disease-relevant macromolecular complexes without having to generate a single crystal are
very appealing, and cryo-EM is becoming a part of lead generation in more and more research departments. The introduction of direct electron detectors, the resolution and range of biological molecules amenable to single particle cryo-EM, have enabled
this.
12:00 pm Sponsored Presentation (Opportunity Available)
12:30 Transition to Lunch
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Session Break
1:45 - 3:15
Lgr5 Stem Cell-Based Organoids in Human Disease
Hans Clevers, MD, PhD,
Principal Investigator of Hubrecht Institute and Princess Máxima Center, CSO of HUB Organoids Technology
Organoid technology opens a range of applications in fields such as physiology, study of disease, drug development and personalized medicine. Human organoids represent excellent disease models, be it infectious, hereditary or malignant Eventually,
cultured mini-organs may be used to replace transplant organs from donors. I will describe how we originally created ‘mini-guts’ via 3D culture systems of stem cells of the small intestine and colon, and then expanded the technology to
virtually all human organs.
Systematically Drugging Ras
Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine
K-Ras is a small GTPase that is mutated in pancreatic (90%), colon (50%), and lung (30%) carcinomas. Downregulation of activated Ras reverses the transformed phenotype of cells and results in the dramatic regression of tumors in murine xenograft models.
Thus, K-Ras inhibition represents an attractive therapeutic strategy for many cancers. In this presentation, I will discuss our efforts to directly target Ras at two sites and target SOS, a molecular partner of Ras, with activators and inhibitors.
3:15 Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 Chairperson’s Remarks
Gottfried Schroeder, PhD, Senior Scientist, Department of Pharmacology, Merck Research Labs Bo
4:05 Next-Generation Inhibitors of Bruton’s Tyrosine Kinase (BTK) and Clinical Trial Results of BIIB068, a Selective, Potent, Reversible BTK Inhibitor
Bin Ma, PhD, Senior Scientist, Medicinal Chemistry, Biogen
Covalent modification of BTK has been proven to be beneficial for cancer patients with multiple drugs on market while their safety profiles are concerned for autoimmune disease indications. A reversible non-covalent BTK inhibitor will have the promise
to address this unmet need. We will report our discovery of BIIB068, an exquisitely selective, potent, reversible BTK inhibitor, together with the med chem strategy and Phase I clinical results.
4:35 Talk Title to be Announced
Rachel Palte, PhD, Senior Scientist, Computational and Structural Chemistry, Merck & Co.5:05 Find Your Table, Meet Your Moderator
5:10 Roundtable Breakout Discussions - View Details
TABLE: Advances and Challenges in Macrocyclic Peptide Therapeutic Development
Moderator: Vincent Guerlavais, PhD, New Modalities, Drug Discovery Consultant
TABLE: Comparing New Biophysical Methods: When to Use What
Moderator: Scott Cowen, PhD, Independent Medicinal Chemistry Consultant
TABLE: Designing and Optimizing Small Molecule Protein Degraders
Moderators: Joe Patel, PhD, Director, Biochemistry, Biophysics & Crystallography, C4 Therapeutics, Inc.
Guangrong Zheng, PhD, Associate Professor, Department of Medicinal Chemistry, College of Pharmacy, University of Florida
5:45 Reception in the Exhibit Hall with Poster Viewing
6:45 Close of Day
Day 1 | Day 2 | Day 3 |
Download Brochure
Thursday, June 4
The final day of the Expanding Chemical & Druggable Space conference highlights the use of targeted protein degradation using proteolysis-targeting chimeric molecules (PROTACs) for disrupting protein-protein interactions and hijacking the
ubiquitin-proteasome system. The talks discuss the development and optimization of a new generation of protein degrader molecules for diverse therapeutic applications.
8:00 am Registration Open and Morning Coffee
8:30 - 9:40 Applications of Artificial Intelligence in Drug Discovery – Separating Hype from Utility
Patrick Walters, PhD, Senior Vice President, Computation, Relay Therapeutics
Over the last few years, there has been tremendous interest in the application of artificial intelligence and machine learning in drug discovery. Ultimately, the success of any predictive model comes down to three factors: data, representation,
and algorithms. This presentation will provide an overview of these factors and how they are critical to the successful implementation and deployment of AI methods.
9:40 Coffee Break in the Exhibit Hall with Poster Viewing
10:25 Chairperson’s Remarks
Jessie Hsu, PhD, Oncology R&D, Senior Scientist, Bioscience, AstraZeneca Pharmaceuticals
10:30 EED-Targeted PROTACs Degrade EED, EZH2, and SUZ12 in the PRC2 Complex
Jessie Hsu, PhD, Oncology R&D, Senior Scientist, Bioscience, AstraZeneca Pharmaceuticals
The polycomb repressive complex 2 (PRC2) is frequently deregulated in cancer. We have discovered a highly potent and selective EED-targeted PROTAC that can inhibit PRC2 activity. The PROTACs target EED and its associated proteins including EZH2
and SUZ12 for elimination and inhibit cell proliferation in PRC2-dependent cancer cells.
11:00 Discovery of Bcl-xL Degraders: A PROTAC Strategy for Tissue-Selective Targeting
Guangrong Zheng, PhD, Associate Professor, Department of Medicinal Chemistry, College of Pharmacy, University of Florida
Bcl-xL plays a key role in cancer cell survival. However, development of drugs targeting Bcl-xL has been thwarted by the on-target platelet toxicity because platelets depend on Bcl-xL to maintain their viability. To circumvent this toxicity, we
have applied the proteolysis targeting chimera (PROTAC) technology to design small-molecules that target Bcl-xL to E3 ligases for degradation. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve
tissue selectivity.
11:30 Expanding the Chemical Space of PROTACs with Novel E3 Ligase Ligands
Kumar Suresh, PhD, Senior Director R&D, Progenra, Inc.
Chemical knock-down of proteins by PROTACs is a paradigm shift in the drug discovery field. Currently, PROTACs based on Cereblon, VHL, HDM2 and cIAPs have been exploited by medicinal chemists to degrade a limited set of therapeutic targets. By
focusing on novel ubiquitin ligases, Progenra has discovered entirely new classes of PROTACs with applications in oncology, inflammation, and neuroscience.
12:00 pm Sponsored Presentation (Opportunity Available)
12:30 Transition to Lunch
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing
2:00 Chairperson’s Remarks
Joe Patel, PhD, Director, Biochemistry, Biophysics & Crystallography, C4 Therapeutics, Inc.
2:05 Finding a Way Out of the Labyrinth: Degrader-Induced Ternary Complex Modeling
Joe Patel, PhD, Director, Biochemistry, Biophysics & Crystallography, C4 Therapeutics, Inc.
With the exponential growth in the development of targeted protein degraders comes significant challenges for the structural biology and computational modelling communities. Numerous examples now exist in the literature of the exquisite SAR possible
through modifications of these molecules, and this has driven a need to generate atomic-level ternary complex information to assist degrader design and elucidate mechanisms of action. Here we will present our approach combining biophysical
and computational methods to generate weighted models to support medicinal chemistry campaigns.
2:35 FEATURED PRESENTATION: Discovery of Novel Degraders Targeting Oncogenic Proteins
Jian Jin, PhD, Mount Sinai Endowed Professor in Therapeutics Discovery; Professor, Department of Pharmacological Sciences and Department of Oncological Sciences; Director, Mount Sinai Center for Therapeutics Discovery; Icahn School of Medicine
at Mount Sinai
The Jian Jin Laboratory at Mount Sinai is a leader in developing novel small-molecule degraders targeting oncogenic proteins. Our recent progress in this area, including discovery of first-in-class EZH2 and MEK1/2 selective degraders, will be
presented.
3:05 Immunotherapeutic Approaches for Degrading Tau Pathology in Alzheimer’s Disease
Gilbert Gallardo, PhD, Assistant Professor, Hope Center for Neurological Disorders, Washington University School of Medicine
Alzheimer’s disease is a tauopathy and the leading cause of dementia worldwide with no disease-modified treatments currently available; however, an emerging therapeutic approach is anti-tau immunotherapies. While conventional immunotherapies
are promising, they are limited to targeting extracellular proteins, whereas the majority of pathological tau remain in the cytosol of cells. Therefore, we have engineered anti-tau intrabodies for expression intracellularly that contain distinct
tags that shuttle tau to either the proteasome or lysosome for degradation.
3:35 Close of Conference
Day 1 | Day 2 | Day 3 |
Download Brochure