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

DIVERSITY-ORIENTED PLATFORMS

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.

9:10 Sponsored Presentation (Opportunity Available)

9:40 Networking Coffee Break

10:05 Challenges and Promise of Phage Display for Peptide Mimetics

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

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.

11:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:20 pm Session Break

DNA-ENCODED LIBRARIES (DEL)

1:15 Chairperson’s Remarks

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

1:20 The Evolving Lead Discovery Toolbox and Integration of Discovery Tactics

Christopher B. Phelps, PhD, Principal Scientist, Medicinal Science and Technology, GlaxoSmithKline

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

Brian 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

Dominik 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).

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

Moderator: Barry Morgan, PhD, CSO, HitGen

Panelists to be Announced

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


4:30 Welcome Remarks from Lead Conference Director

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

4:35 Plenary Technology Spotlight Presentation to be Announced

5:05 Plenary Keynote Introduction (Sponsorship Opportunity Available)

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

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

Matt 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 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

Rudi 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 Case Study: Optimization of a DEL Drug Candidate, RIP1K

Heather O’Keefe, PhD, Investigator, Medicinal Science and Technology, GlaxoSmithKline

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

Dean 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

* The program is subject to change without notice, due to unforeseen reason.