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

Recommended Short Course*

SC5: Chemoproteomics Enabling Drug Discovery - Detailed Agenda

*Separate registration required.

Tuesday, June 2

10:00 am Main Conference Registration Open

MACROCYCLICS

11:15 Chairperson’s Remarks

Tomi Sawyer, PhD, President, Maestro Therapeutics

11:25 Development of Macrocyclic Peptides for Intracellular Targets

Tellers_DavidDavid 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

Pye_CameronCameron 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

Pei_DehuaDehua 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

ENCODED LIBRARIES

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 

Fairbrother_WayneWayne 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

Kodadek_ThomasThomas 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

Arico-Muendel_ChrisChristopher 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


PLENARY KEYNOTE SESSION

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.

Sarwar_NadeemModerator: 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

Wednesday, June 3

7:30 am Registration Open and Morning Coffee

FRAGMENT-BASED DRUG DESIGN

8:10 Chairperson’s Remarks

Scott Cowen, PhD, Independent Medicinal Chemistry Consultant

8:15 Optimizing a Fragment Hit into Undruggable Space: A Case Study

Dietrich_J_-_CopyJustin 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

Valenzano_ChiaraChiara 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

NEW BIOPHYSICAL TECHNIQUES FOR DRUG LEAD GENERATION

11:00 SAR by 19F NMR: Using Protein-Observed Fluorine NMR for Targeting Protein Complexes

Pomerantz_WilliamWilliam 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

Han_SeungilSeungil 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


PLENARY KEYNOTE SESSION

1:45 - 3:15

Lgr5 Stem Cell-Based Organoids in Human Disease

Clevers_HansHans 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

Fesik_StephenStephen 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

ORTHOGONAL APPROACHES FOR LEAD GENERATION

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

Ma_Bin_-_CopyBin 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

Thursday, June 4

8:00 am Registration Open and Morning Coffee


PLENARY KEYNOTE SESSION

8:30 - 9:40 Applications of Artificial Intelligence in Drug Discovery – Separating Hype from Utility

Walters_PatrickPatrick 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

DISCOVERY OF NOVEL PROTAC-BASED DEGRADERS

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

Hsu_JessieJessie 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

Zheng_GuangrongGuangrong 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_SureshKumar 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

OPTIMIZING & ENGINEERING TARGETED DEGRADATION

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

Patel_JoeJoe 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

Jin_JianJian 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

Gallardo_GilbertGilbert 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