Encoded Libraries for Small Molecule Discovery Icon

Cambridge Healthtech Instituteの第5回年次会議

Encoded Libraries for Drug Discovery
(創薬向けエンコードライブラリ)

新しい化学物質向け化学空間の拡大

2023年4月12 - 13日

 

この会議では、創薬化学者が集まり、最新の創薬リード生成戦略の1つであるDNAエンコードライブラリ(DEL)について議論し、最新情報を把握します。DELは、化学空間を拡大し、特定の標的に対して多くのヒットを迅速に生成するのに有効なことが証明されていますが、スクリーニングできる標的の種類には限界があり、DELスクリーニングによって提供される豊富なヒットから有望な薬物リードを選択することが困難な場合もあります。このような課題に対する可能な解決策について話し合い、ケーススタディをご紹介します。

4月12日(水)

Registration Open12:00 pm

Dessert Break in the Exhibit Hall with Poster Viewing12:45 pm

Welcome Remarks1:30 pm

DNA-ENCODED LIBRARY INNOVATIONS
DNAエンコードライブラリ(DEL)のイノベーション

1:35 pm

Chairperson's Remarks

Nicholas Simmons, Chemisty Leader, DNA Encoded Library DEL, Janssen Pharmaceuticals Inc

1:40 pm

FEATURED PRESENTATION: Accelerated Screening and Optimization of DEL-Hits: Cleavable Linker Platform (CLiP)

Anokha S. Ratnayake, PhD, Principal Scientist, Design and Synthesis Sciences, DNA Encoded Library Technology Group, Pfizer Global R&D Groton Laboratories

In recent years, we have seen an increase in demand for screening our DNA-Encoded Libraries (DELs) for hit identification across the Pfizer portfolio. To increase efficiency of these campaigns, we optimized our DEL-hit follow-up platform to enable both on-DNA and off-DNA hit confirmation in a seamless manner using cleavable linkers (DEL-CLiP). This talk will detail the operation and application of DEL-CLiP highlighting its impact on expediting the hit-to-lead optimization process.

2:10 pm

Activity-Based and Cellular Analysis Technology for Encoded Libraries

Brian M. Paegel, PhD, Professor, Pharmaceuticals Sciences, University of California, Irvine

I provide updates on activity-based DEL technology, which interfaces solid-phase “OBOC” libraries with HTS-style activity assay. Our recent efforts focus on three thematic areas: 1) the discovery of translation modulators as a general strategy for interrogating the proteome via one universal biochemical activity assay, 2) development of pharmacokinetic assays for analyzing “beyond Rule of 5” libraries, and 3) novel 3D tissue culture strategies to enable cell-based DEL screening.

2:40 pm Talk Title to be Announced

Guansai Liu, Vice President and Head of Discovery Chemistry, HitGen

Refreshment Break in the Exhibit Hall with Poster Viewing3:10 pm

4:00 pm

Using DNA-Encoded Libraries to Find Potent and Selective Inhibitors to Phosphodiesterases

Rachael Jetson, PhD, Senior Director, Lead Discovery, Valo Health

Phosphodiesterases (PDEs) play critical roles in cellular signaling, making them desirable therapeutic targets. Finding isoform-specific inhibitors can be essential to limiting adverse side effects in drug discovery. DEL platforms allow for simultaneous interrogation of numerous conditions in parallel making it an ideal platform to find selectivity. This presentation will highlight how we leveraged the Valo DEL platform to find potent and selective inhibitors for a PDE program.

4:30 pm

Expanding the Scope of DNA-Encoded Libraries

Meghan Lawler, PhD, Director Affinity Technology, Biology, Anagenex

At Anagenex, we are successfully developing methods via both machine learning and in-lab experimental design. Herein, we will discuss how our new methods have enabled us to leverage both active and inactive molecules towards the drug discovery pipeline as well as establish binding compounds for a wide range of protein classes including DNA-binding proteins.

In-Person Group Discussions5:00 pm

IN-PERSON GROUP DISCUSSION:

Deploying DEL in Lead Discovery

Meghan Lawler, PhD, Director Affinity Technology, Biology, Anagenex

Jeff A. Messer, Director, Analytics, Encoded Libraries Technology, GlaxoSmithKline

Brian M. Paegel, PhD, Professor, Pharmaceuticals Sciences, University of California, Irvine

  • Improving “off-DNA” hit confirmation rates-or are they good enough?  
  • Machine learning with DEL data: is it living up to the hype?  
  • Could more be happening in the pre-competitive space?  
  • DEL libraries: partnering vs. in-house

Close of Day5:45 pm

Dinner Short Course*6:15 pm

SC7: DNA-Encoded Libraries

*Premium Pricing or separate registration required. See Short Courses page for details.

4月13日(木)

Registration Open7:15 am

Diversity in Chemistry Breakfast Discussion (Sponsorship Opportunity Available)7:45 am

IN-PERSON GROUP DISCUSSION:

Diversity in Chemistry beyond Molecules: Gender and More

Michelle Arkin, PhD, Chair and Distinguished Professor, Pharmaceutical Chemistry & Director, Small Molecule Discovery Center, University of California, San Francisco

Thomas P. Garner, PhD, Principal Scientist, Biophysics, Genentech, Inc.

Justyna Sikorska, PhD, Associate Principal Scientist, Mass Spectrometry & Biophysics, Merck

We encourage all to attend this moderated, audience-interactive discussion session. When it comes to increasing diversity among scientists, there continues to be a drop-off as one moves higher in leadership. Where do systemic challenges remain, what is your experience, and how can we continue to equalize the system?   

Topics may include below, but will be guided by audience input: 

  • Where does the 'drop-off' of women in the chemistry career progression pipeline occur and why? 
  • How did the pandemic and other sea changes in the past three years bring us closer to or further from equality? 
  • What issues arose that you thought were solved? 
  • Diversity in life paths should include us all - how are men and nonbinary scientists being included? 
  • Intersectionality and equality - what is the experience of women of color, first-generation women scientists, and others?

PLENARY KEYNOTE SESSION
基調講演(プレナリーセッション)

8:30 am

Plenary Welcome Remarks from Lead Content Director with Poster Finalists Announced

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

Plenary Keynote Introduction (Sponsorship Opportunity Available)8:35 am

8:45 am PLENARY:

Reflections on a Career as a Medicinal Chemist in Drug Discovery

Nicholas A. Meanwell, PhD, Vice President (recently retired), Small Molecule Drug Discovery, Bristol Myers Squibb Co.

A successful drug candidate depends on many factors: creativity of scientists involved, effective collaboration and commitment by the team, and the quality of the compound advanced. I reflect on a 40-year career pursuing the discovery of drug candidates designed to address unmet medical need in the cardiovascular, CNS, and viral diseases therapeutic areas and share undervalued strategies and other synthetic chemistry approaches for overcoming specific medicinal chemistry challenges.

Coffee Break in the Exhibit Hall with Poster Viewing9:30 am

NEW DNA-ENCODED LIBRARY APPLICATIONS
新しいDNAエンコードライブラリ(DEL)の応用

10:20 am

Chairperson's Remarks

Sylvie K. Sakata, PhD, Executive Director & Head, External Research Solutions, Pfizer Inc.

10:25 am

Utilizing DEL as a Primary Discovery Engine for Targeted Protein Degradation

Christopher B. Phelps, PhD, Vice President and Head, Early Discovery, Nurix Therapeutics, Inc.

Targeted protein degradation has emerged as a promising new modality for addressing previously undruggable targets. DNA-Encoded Libraries offer significant and specific advantages for identifying ligands for bifunctional degraders. Nurix has designed and deployed an integrated DEL discovery pipeline to harness novel ligases and degrade both traditional and challenging targets.

10:55 am

DEL Selections for Molecular Glues

Audrey E. Tolbert, PhD, Investigator, Encoded Library Technology Biology, GSK

Molecular glues are an established modality for therapeutic intervention. There is high interest in identifying putative molecular glues to modulate protein-protein interactions involved in protein degradation, cellular localization, or activity. DNA-encoded libraries allow for the screening of billions of small molecules as potential molecular glues. These molecular glues are identified via binding enrichment in the presence of both proteins over-enrichment in selections with a single protein.

11:25 am We have your leads!

Ghotas Evindar, PhD, Senior Vice President, Discovery, Discovery, 1859 Inc.

1859 is transforming how the Life Science industry discovers new medicines by combining custom chemistry capabilities, miniaturized screening technology, and machine learning to generate novel, diverse, and bioactive Lead molecules through iterative drug discovery. With our ability to predict new chemical starting points, our platform can address new therapeutic targets, or find novel matter for those previously explored, to bring new medicines to patients in need. 

11:40 am

DNA-Encoded Libraries for the Identification of Covalent Inhibitors

Xiaojie Bruce Lu, PhD, Professor & Principal Investigator, Chemical Biology Research Center, Chinese Academy of Sciences

We have designed and synthesized a series of covalent libraries for the identification of the covalent inhibitors. We describe three different proteins for which we identified inhibitors by heterocycle scaffold-based DELs (https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.2c00127). 

Presentation to be Announced12:10 pm

Transition to Lunch12:40 pm

12:50 pm LUNCHEON PRESENTATION:DNA-encoded libraries for the discovery of small-molecule hits

Alex Satz, PhD, Senior Director DEL Strategy and Operations, WuXi Biology, WuXi AppTec

DNA-Encoded library (DEL) screening is now commonly used in the pharmaceutical industry to find novel chemical matter that modulates protein targets of interest.  Point-by-point I will discuss the primary challenges and limitations of DEL screening, and concisely state the current abilities of the technology and then its potential.  

Refreshment Break in the Exhibit Hall with Poster Awards Announced1:20 pm

Poster Award (Sponsorship Opportunity Available)

ENCODED LIBRARIES FOR ORAL MACROCYCLICS
経口大環状分子のエンコードライブラリ

2:00 pm

Chairperson's Remarks

Thomas J Tucker, Principal Scientist, Medicinal Chemistry, Merck & Co Inc

2:05 pm

Discovery and Optimization of an Oral PCSK9 Macrocyclic Inhibitor from mRNA Display Screening 

Thomas J Tucker, Principal Scientist, Medicinal Chemistry, Merck & Co Inc

This talk will highlight the discovery efforts from mRNA display screening hits to a tricyclic peptide PCSK9 inhibitor drug candidate, which demonstrated its pharmacodynamic effects similar to the FDA-approved, parenterally dosed anti-PCSK9 mAb, with the advantage of oral administration using lipidic dosing vehicle Labrasol.

2:35 pm

Improved DNA-Encoded Libraries for Macrocyclic Peptides

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

I will discuss my lab's research which touches on macrocycles (DELs) and a strategy we patented for creating super pure DELs which should work out much better in DEL selections by improving signal:noise.

3:05 pm

Libraries and Display Selection for Macrocycles with Better Membrane Permeability

Hiroaki Suga, PhD, Professor Chemistry, Chemical Biology & Biotechnology, University of Tokyo

We design libraries of macrocycles aiming at generating better cell membrane permeability and apply to the RaPID selection against protein target of interest.

Networking Refreshment Break3:35 pm

CHOOSING DEL's GREATEST HITS
DELのベストヒットを選択

3:55 pm

Facilitating DEL Hit Triage: Estimating Data Noise Level via Selection Replicate Samples 

Hongyao Zhu, PhD, Associate Research Fellow, Machine Learning and Computational Sciences, Pfizer Inc.

An approach to estimating data noise level has been developed by including replicate samples in DEL selections. The noise level is seen to be dependent on sequencing depth and specific selection conditions. The estimated noise cutoff can be used to remove compounds with low sequence reads for DEL hit triage, which greatly reduces (>100-fold) challenges encountered in DEL data analysis without impacting interpretation of the results.

4:25 pm

Transforming DNA-Encoded Library Screening from Qualitative to Quantitative Outcomes

Ching-Hsuan Tsai, PhD, Director, Relay Therapeutics, Inc.

DEL screening has typically classified enriched compounds as binder/not binder, with a highly variable confirmation rate after off-DNA synthesis. A better understanding of the impacts of selection variables on the output of DEL could improve off-DNA confirmation rates and provide more useful datasets for ML. Here, tool compounds of known different affinities are used to validate selection techniques to improve the quantitative prediction of on-DNA affinity from DEL selections.

4:55 pm

Applying Machine Learning to DEL Hit Selection

Patrick Neal, PhD, Analyst, Chemoinformatics, GlaxoSmithKline

Automated structure-activity relationship (SAR) analysis has historically relied on clustering, Quantitative-SAR models, or machine learning to identify potent medicines from high-throughput screening assays. We propose a new straightforward scaffold-based approach for identifying enriched chemical series. Our technique picks chemotypes by breaking down hits into a network of scaffold and scaffold fragments, then uses rank-choice voting to select which scaffolds best represent their exemplars and confer enrichment.

Close of Conference5:25 pm

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