Cambridge Healthtech Institute’s Inaugural

Directed Evolution-Based Drug Discovery

DNA Encoded Libraries and Other Diversity Oriented Platforms

April 9-10, 2019

Directed evolution approaches for drug discovery use genetic strategies (DNA-encoded, RNA-encoded or phage-based) to create very large but specific libraries of molecules whose amplification is driven by the target of interest. The theory was established decades ago but recently applications in early stage drug discovery have become more widespread. A few drug candidates arising from directed evolution campaigns are now in clinical trials. A bottleneck however of these diversity-oriented strategies is figuring out which hits to focus on from the many hits that are produced by these approaches. Cambridge Healthtech Institute's Inaugural Directed Evolution-Based Drug Discovery conference will cover challenges, innovations, best practices and case studies in three of the major diversity-oriented platforms: DNA encoded libraries, mRNA-directed technologies and phage display.

Final Agenda

 

Tuesday, April 9

7:00 am Registration Open and Morning Coffee ( 20 C/D Foyer) 

DIVERSITY-ORIENTED PLATFORMS
31A

8:00 Welcome Remarks

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Sepideh Afshar, PhD, Principal Research Scientist, Department of Protein Engineering, Eli Lilly and Company

8:10 FEATURED PRESENTATION: One Bead One Compound Introduction and Innovations: Library against Library Screening

Kit S. Lam, MD, PhD, Distinguished Professor and Chair, Department of Biochemistry and Molecule Medicine, University of California Davis

I start with an overview of the one-bead-one-compound (OBOC) platform which enables rapid creation of chemically encoded high diversity combinatorial synthetic peptide, peptidomimetic, macrocyclic or small molecule libraries on micro-beads. Such libraries can then be efficiently screened for binding against molecular targets such as soluble proteins, phages, bacteria, and live cells. Screening can also be achieved with cell-based assays for cellular functions and signaling. I end by describing a method to greatly increase the diversity of molecular interactions, by using a phage-display protein domain library derived from cancer cells as probes to screen encoded OBOC small molecule libraries.

Wuxi-Apptec 9:10 Unleashing DNA-Encoded Library Technology: Drug Discovery and Beyond

Kuai_LetianLetian Kuai, PhD, Senior Director, Head of Biology & Informatics,  WuXi AppTec

DNA Encoded Library (DEL) technology offers an unprecedented capability for researchers to synthesize and analyze numerically large chemical libraries to identify hits rapidly with very low cost. The natural strength of this technology to discover affinity molecules with SAR could lead to a wide range of potential applications.

 

9:40 Networking Coffee Break

10:05 Challenges and Emerging Approaches in Peptide Phage Display and its Application in Targeting Stem Cell Receptors

Rami N. Hannoush, PhD, Principal Scientist, Group Leader, Early Discovery Biochemistry, Genentech

10:35 FEATURED PRESENTATION: Unnatural Amino Acids for Exotic Macrocyclic Peptides and Targeting IL6R as a Case Study

Hiroaki Suga, PhD, Professor, Department of Chemistry, School of Science, The University of Tokyo

This talk discusses recent advances in the discovery of bioactive macrocyclic pseudo-natural peptides containing exotic amino acids using a discovery platform, the RaPID system. This system enables for extremely “rapid” affinity-based screening of pseudo-natural peptides against proteins of interest from a library consisting of a trillion different short sequences, usually less than 15 residues. Yet the discovered molecules exhibit remarkable bioactivity, often single digit nM or sub nM of dissociation constants.

Patsnap 11:35 Luncheon Presentation: Synthetic Biology and the Vital Role of Intellectual Property

Christopher Bustos, Solutions Consultant, PatSnap

DNA-ENCODED LIBRARIES (DEL)

1:15 Chairperson’s Remarks

Svetlana Belyanskaya, PhD, Encoded Library Technologies, R&D Platform Technology & Science, GSK Boston

1:20 Discovery and Optimization of Potent and Selective TYK2 Pseudokinase Inhibitors through DNA-Encoded Library Technology

Evindar_GGhotas Evindar, PhD, Head, Drug Design and Selection, Medicinal Science & Technology, GlaxoSmithKline

DNA-encoded chemical library screening is an established platform for identifying hits for therapeutic targets. At GSK the platform is utilized broadly to screen a wide range of therapeutic targets than any other screening methods including HTS. Herein, I will provide an overview of the ELT platform followed by a case study application of the platform to the discovery of a potent and selective class of TYK2 pseudokinase inhibitors. The talk will also describe hit to lead optimization of the chemical series through use of both ELT selection data and an obtained X-ray crystal structure of an early lead molecule.

1:50 Activity-Based DNA-Encoded Libraries Screening Technology

Paegel_BBrian Paegel, PhD, Associate Professor, Department of Chemistry, Department of Molecular Medicine, Scripps Research

Combinatorial DNA-encoded library (DEL) technology surveys vastly larger and more diverse chemical spaces than standard HTS collections, but relies on affinity selection to identify hits. We have developed solid-phase DEL synthesis protocols and engineered microfluidic screening technology for conducting activity-based screens using these DELs. I will describe screening results against several common target enzyme classes as well as in vitro translation as a stepping stone toward cellular screening.

2:20 Employing Photoredox Catalysis for the Synthesis of DNA-Encoded Libraries

Koelmel_DDominik Koelmel, PhD, Senior Scientist, DNA-Encoded Libraries, Pfizer

The development of photoredox catalysis has had a profound impact on the synthetic chemistry community, allowing for the facile preparation of complex compounds from rather simple and readily available starting materials. However, photoredox catalysis has hitherto not been used in the context of DNA-encoded chemistries. Our first proof-of-concept studies have now demonstrated that photoredox catalysis can be a valuable reaction platform for the preparation of DNA-encoded libraries (DELs).

Hitgen 2:50 Panel Discussion: 25 Years of DNA Encoded Libraries: Where are We?

Moderator: Barry Morgan, PhD, CSO, HitGen, Ltd.

Panelists:
Dean G. Brown, PhD, Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

Ghotas Evindar, PhD, Head, Drug Design and Selection, Medicinal Science & Technology, GlaxoSmithKline
Brian Paegel, PhD, Associate Professor, Department of Chemistry, Department of Molecular Medicine, Scripps Research

Hiroaki Suga, PhD, Professor, Department of Chemistry, School of Science, The University of Tokyo

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing


4:30 Plenary Session Welcome Remarks from Event Director

Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute

4:35 Plenary Technology Spotlight Molecular Modelling for the Masses: Orion

Hawkins_PaulPaul Hawkins, Head, Scientific Solutions, OpenEye Scientific

The advent of cloud computing has been transformative for many fields that utilize computation, including drug discovery. The cloud offers robust, elastic, and scalable compute resources through a browser, decreased IT overhead, costs, and time to obtain actionable results. In this presentation I illustrate how the cloud, and in particular OpenEye’s web-based platform Orion, is democratizing molecular modelling by providing easy to se access to cutting-edge molecular design tools coupled with essentially unlimited compute resources.

 

5:05 Plenary Keynote Introduction

 

Steadman_VickyVicky Steadman, PhD, Business Line Leader, Integrated Drug Discovery, Eurofins Discovery (formerly Eurofins Pharma Discovery Services)


 

5:10 Plenary Keynote: Chemical Biology of Proteostasis

Jack Taunton, PhD, Professor, Department of Cellular and Molecular Pharmacology, University of California San Francisco

We have recently discovered several macrocyclic compounds that potently and selectively modulate protein homeostasis. I will discuss our recent efforts to unravel their molecular mechanisms.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

 

Wednesday, April 10

7:30 am Continental Breakfast Breakout Discussions - View All Breakouts

In these sessions, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers.

Topic: Genetically/DNA Encoded Libraries of Macrocyclic Peptides

Moderator: Rudi Fasan, PhD, Professor, Department of Chemistry, University of Rochester

  • Current and emerging strategies for generation and screening of genetically encoded macrocyclic peptides
  • Applications/target classes: When to use which platform?
  • Challenges and opportunities for future development

Topic: Phage Display

Moderator: Sepideh Afshar, PhD, Principal Research Scientist, Department of Protein Engineering, Eli Lilly and Company

  • What is next for phage display platforms?
  • Using phage display to identify peptides that cross biological barriers
  • Integrating phage display with other display platforms to overcome its limitations

Topic: DNA-Encoded Library Technology

Moderator: Brian Paegel, PhD, Associate Professor, Department of Chemistry, Department of Molecular Medicine, Scripps Research

  • DNA-compatible reaction development
  • Scaffold design
  • Screening strategies

ENCODED LIBRARY APPROACHES

8:30 Chairperson’s Remarks

Brian Paegel, PhD, Associate Professor, Department of Chemistry, Department of Molecular Medicine, Scripps Research

8:35 Finding the Right Fit: An in vitro Selection Approach for Optimizing Peptide Scaffolds for the Discovery of Peptide Leads

Hartman_MMatt Hartman, PhD, Associate Professor, Chemistry, Masey Cancer Center, Virginia Commonwealth University

Diverse libraries of macrocyclic peptides are a potential storehouse for therapeutic reagents against many different PPI targets. But it is often challenging to predict what the best macrocyclic scaffold would be for a particular target. Using mRNA display, we have generated trillions of cyclic and bicyclic peptides encompassing a variety of topologies. We have then used these libraries to select protein binders. The hits exhibit interesting and unique scaffold preferences.

9:05 Characterization of Specific Naa50 Inhibitors Identified using a DNA Encoded Library: a Lead-Finding Case Study for a Challenging Target

Pei-Pei_KPei-Pei Kung, PhD, Associate Research Fellow, Medicinal Chemistry, Pfizer San Diego

The catalytic site of Naa50 enzyme is considered difficult to drug because of its large binding site and lower hydrophobicity compared to typical druggable targets. We screened a 22 billion-member DNA-encoded library to identify novel Naa50 inhibitors. This provided several hits that were confirmed to be specific Naa50 binders/inhibitors. Crystal structures of these hits in complex with the Naa50 protein were obtained that helped explain their mechanism of action.

9:35 Coffee Break in the Exhibit Hall with Poster Awards Announced

Poster Awards Sponsored by Domainex

ENCODED LIBRARY APPLICATIONS

10:30 Design and Evolution of Macrocyclic Peptide Inhibitors of the Hedgehog Signaling Pathway

Fasan_RRudi Fasan, PhD, Professor, Department of Chemistry, University of Rochester

The Hedgehog signaling pathway plays a central role during embryonic development and its aberrant activation has been implicated in the development and progression of several human cancers. This talk will describe the design and evolution of macrocyclic peptides capable of inhibiting the Hedgehog pathway by targeting and disrupting the Hedgehog protein/Patched interaction, the most upstream event in the ligand-induced activation of this cell signaling pathway.

11:00 NEW: Engineered TrpB Biocatalysts for the Modular Synthesis of Noncanonical Amino Acids

David K. Romney, PhD, Postdoctoral Fellow, Laboratory of Frances Arnold, Division of Chemistry and Chemical Engineering, California Institute of Technology

Noncanonical amino acids (ncAAs) are widely used as pharmaceutical precursors and biological probes. However, they often require multi-step synthetic routes that involve expensive transition-metal catalysts and hazardous reaction conditions. Consequently, many ncAAs are not commercially available or are prohibitively expensive. By using protein engineering techniques such as directed evolution, we developed a suite of biocatalysts based on the tryptophan synthase β-subunit (TrpB). These catalysts provide direct access to almost 100 ncAAs from readily available materials.

11:30 DEL for Membrane Proteins: Case Study of a GPCR

Brown_DDean G. Brown, PhD, Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

This talk compares a DNA-encoded library screen to identify antagonists at protease activated receptor (PAR2) with a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites. These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.

12:00 pm Close of Conference