Cambridge Healthtech Institute’s 2nd Annual

Encoded Libraries for Small Molecule Discovery
( 小分子藥物新藥發現的編碼庫 )

Expanding Chemical Space for New Drug Leads

2020年4月15-16日



DNA-encoded libraries (DELs) exploit chemical synthesis to create large numbers of compounds that can be simply and rapidly screened based on affinity-binding. DEL innovations have expanded the range of potential chemical compounds that can be screened for new drug development, thus creating drug leads better suited for newer targets such as intracellular protein complexes. However, while compound hits arising from DEL screens are typically bigger and more potent, they are often harder for the medicinal chemist to work with. Another challenge is how to integrate DEL applications into the drug discovery process. Cambridge Healthtech Institute’s 2nd Annual Encoded Libraries for Small Molecule Discovery conference (refocused from last year’s Directed Evolution conference) convenes early drug discovery scientists to discuss these challenges and more such as which targets are best suited for DEL approaches, best ways to screen the libraries, hit selection and methods for obtaining good quality starting point for medicinal chemistry optimization campaigns.

Final Agenda

4月15日(三)

12:30 pm Registration Open

12:45 Dessert Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

Library Sampling of Chemical Space

1:30 Welcome Remarks

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

1:35 Chairperson’s Opening Remarks

Brian PaegelBrian Paegel, PhD, Professor, Department of Chemistry, University of California, Irvine


1:40 Dual-Display DEL Technology and Beyond

Joerg ScheuermannJoerg Scheuermann, PhD, Senior Lecturer, Chemistry & Applied Biosciences, ETH Zurich


DNA-Encoded Libraries (DELs) of dual-display setup have been used for discovering simultaneously binding fragments. Furthermore, dual-display can now be combined with conventional split-and-pool derived single-display libraries yielding very large high-quality DELs by combinatorial assembly. Such libraries feature large structural diversity and selection results with these libraries will be presented for a panel of target proteins.

2:10 A Solution Phase Platform to Characterize Chemical Reaction Compatibility with DNA-Encoded Chemical Library Synthesis

Anokha RatnayakeAnokha Ratnayake, PhD, Principal Scientist, Design and Synthesis Sciences, DNA Encoded Library Technology (DELT) Group, Pfizer

The growing scope of chemistries for DNA-encoded chemical library (DECL) synthesis has intensified the need for quantitative methods for validating their compatibility with DNA. We have developed a comprehensive approach for the assessment of chemical fidelity (reaction yield and purity), encoding fidelity (ligation efficiency), and readability (DNA compatibility), revealing the fate of the DNA-tag during DECL chemistry from a single platform. I will describe its utility in screening on-DNA chemistries.

2:40 Target Class-Focused DEL Libraries

Raphael FranziniRaphael Franzini, PhD, Assistant Professor, Medicinal Chemistry, University of Utah

DNA-encoded libraries (DELs) are widely used in drug discovery. Large generic DEL platforms are typically used for these purposes. While these methods have been proven effective, such platforms are expensive to make and can be associated with technical problems such as library heterogeneity and undersampling. We tested the possibility of generating DELs that are focused to specific protein classes allowing to achieve high screening productivity at low cost and providing reliable structure-activity information. The concept was demonstrated with a library targeting proteins with NAD(+)-binding pockets.

3:10 Sponsored Presentation (Opportunity Available)

3:40 Refreshment Break and Book Signing in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

4:30 Methods for Estimating Affinity from DEL Primary Selection Data

Justin HallJustin Hall, PhD, Principal Scientist, Structural Biology & Biophysics, Pfizer

It is typical to find more candidate binders from DEL selections than is reasonable to pursue. Common practice is to limit synthesis to compounds estimated to be high-affinity binders; of the factors contributing to this estimation, the strength of the sequence signals of a compound is always important. We describe here methods and equations to relate sequence signal to the prospective estimation of compound affinity and chemical yield from DEL selection data.

5:00 New Approaches in the Selection of DNA-Encoded Chemical Libraries

Xiaoyu LiXiaoyu Li, PhD, Associate Professor, Department of Chemistry, The University of Hong Kong

The selections of DNA-encoded chemical libraries (DELs) have been mostly performed with purified recombinant proteins. Recently we have expanded the target scope of DEL by developing several new methods that are capable of selecting DELs against non-immobilized endogenous proteins in cell lysates or on live cells. We will describe the methodology development as well as the applications of these new selection methods.

5:30 Breakout Discussions - View All Breakouts

In this session, 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: DNA-Encoded Library Technology

Moderator: Brian Paegel, PhD, Professor, Department of Chemistry, University of California, Irvine

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

Topic: Future Developments in DEL Technology

Moderator: Joerg Scheuermann, PhD, Senior Lecturer, Chemistry & Applied Biosciences, ETH Zurich

  • How best to speed-up hit validation
  • Ways to quickly identify false positives
  • Single or multiple display of ligands

6:15 Close of Day

6:30 Dinner Short Courses

4月16日(四)

8:00 am Breakfast Plenary Technology Spotlight (Sponsorship Opportunity Available) or Morning Coffee

8:45 Plenary Welcome Remarks from Event Director with Poster Finalists Announced

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

8:55 Plenary Keynote Introduction

Speaker to be Announced, LabTwin


9:00 PLENARY KEYNOTE:

baranPphilTranslational Chemistry

Phil Baran, PhD, Professor, Department of Chemistry, Scripps Research

There can be no more noble undertaking than the invention of medicines. Chemists that make up the engine of drug discovery are facing incredible pressure to do more with less in a highly restrictive and regulated process that is destined for failure more than 95% of the time. How can academic chemists working on natural products help these heroes of drug discovery – those in the pharmaceutical industry? With selected examples from our lab and others, this talk will focus on that question highlighting interesting findings in fundamental chemistry and new approaches to scalable chemical synthesis.

9:45 Coffee Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

Innovations in Approaches to Screening

10:40 Chairperson’s Remarks

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

10:45 Before and After IDO1 ELT Selection: Protein Construct Assessment and High Throughput Binder Confirmation

Eric Shi, PhD, Investigator, Encoded Library Technologies, NCE Molecular Discovery, GlaxoSmithKline

Protein construct assessment before ELT selection is crucial for the success of ELT selection. We utilized affinity selection-mass spectrometry (ASMS), dynamic light scattering, and Bioanalyzer to characterize the constructs and optimize ELT selection conditions with various buffers and temperatures. Many features were successfully selected in the IDO1 ELT selection. To achieve high throughput binder confirmation (HTBC), ASMS was used in the follow-up assay and confirmed 139 ELT primary binders.

11:15 FEATURED PRESENTATION: Off-DNA DNA-Encoded Library Screening Technology

Brian Paegel, PhD, Professor, Department of Chemistry, University of California, Irvine

DNA-encoded libraries (DEL) sample vastly larger and more diverse chemical spaces than standard HTS collections, but rely on affinity selection of DNA-displayed small molecules to identify hits. The DNA tags are a known interference for some targets, particularly nucleic acid-binding proteins. We have developed an off-DNA macromolecular binding analysis using solid-phase DELs, microfluidic droplets, and fluorescence polarization detection. Application to several targets will be discussed.

11:45 Progression of A DNA Encoded Library Hit to an In Vivo Active Lead Series, & Methods for Accessing Encoded Heterocycles

Satz_AlexAlex Satz, Senior Director, DEL Strategy and Operations, Research Services Division, WuXi AppTec

We will discuss the discovery of a selective inhibitor of discoidin domain receptor1 (DDR1) and the progression from a DNA-encoded library hit to an in vivo active lead series, challenges of on-DNA synthesis of highly-functionalized and rigid heterocycles, and present possible solutions using the Pictet-Spengler reaction as an example.

12:00 pm Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery

Jonas Schaefer, PhD, Laboratory Head, Encoded Library Technologies, Novartis Institutes for Biomedical Research, Chemical Biology & Therapeutics (CBT), Novartis Pharma AG

Finding suitable chemical matter with the current compound collections is proving increasingly difficult. Encoded library technologies allow for the rapid exploration of a large chemical space for the identification of ligands for such targets. In the presentation, we will discuss how we apply these platforms in our research, including how we narrow the myriad of hits to a few leads, and why we believe it is beneficial to run both pipelines in house.

12:30 Session Break

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Dessert Break in the Exhibit Hall with Poster Awards Announced (Sponsorship Opportunity Available)

MOVING FROM ENCODED LIBRARY HITS TO DRUG LEADS

2:15 Chairperson’s Remarks

Anokha RatnayakeAnokha Ratnayake, PhD, Principal Scientist, Design and Synthesis Sciences, DNA Encoded Library Technology (DELT) Group, Pfizer


2:20 mRNA/DNA-Encoding Library of Pseudo-Natural Products and RaPID Screening

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


This talk describes the latest development of mRNA/DNA-encoding library of pseudo-natural products derived from Lactazole A and their library display, allowing for the RaPID discovery of de novo ligands/inhibitors against proteins of interest.

2:50 Talk Title to be Announced

Dean BrownDean Brown, PhD, formerly Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca


3:20 PANEL DISCUSSION: What Is the Status of DNA-Encoded Library Technology in Small Molecule Drug Discovery?

DEL technology has attracted significant interest with the practitioners of early-stage drug discovery in the past few years. We’ll assemble a panel of providers and users, and debate the following topics:

  • What is the perspective from “big pharma,” “biotech,” and academia?
  • How does it differ from other “lead discovery” strategies in terms of ROI: Is there synergy?
  • How can the technology be improved – what are the challenges?
  • Questions from attendees

Moderator:

Barry Morgan, PhD, CSO, HitGen, Ltd.

Panelists to be Announced

3:50 Networking Refreshment Break

Encoded Library-Origin Compounds for Oncology

4:20 DEL-Enabled Discovery of Novel MoA and Structurally Unique IDO1 Inhibitors

Bing Xia, PhD, NCE Encoded Library Technologies, RD Medical Science & Technology, GlaxoSmithKline

Indoleamine 2,3-dioxogenase-1 (IDO1) is induced and activated in response to viral and bacterial infection causing a dysfunctional immune response in clearing pathogens. IDO1 inhibitors (IDO1i) have the potential to restore immune function in indications such as cancer and infection. A structurally-unique IDO1i class was discovered through the affinity selection of a novel DNA-encoded library. After additional medicinal chemistry iterations, the compound series was elaborated into potential best in class preclinical molecule.

4:50 Discovery and Application of a Novel Cell Death Mechanism in Oncology

Maria SoloveychikMaria Soloveychik, PhD, Co-Founder and CEO, SyntheX

We developed STX100, a peptide originating from an encoded library, targeting an intracellular protein-protein interaction in the homologous recombination DNA repair pathway. STX100-mediated cell killing is independent of canonical cell death mechanisms; it relies on acute calcium release from its target to elicit cell death. The mechanism translates to in vivo models, where a local delivery of STX100 and a combination of immune checkpoint blockade (ICB) agents can cure established tumors resistant to ICB therapies.

5:20 Talk Title to be Announced

Speaker to be Announced, Nuevolution

5:50 Close of Conference

* 活動內容有可能不事先告知作更動及調整。

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