Cambridge Healthtech Institute’s 15th Annual

Fragment-Based Drug Discovery
( 建置片段藥物設計 )

From Hits to Leads and Lessons Learned

2020年4月14-15日



Fragment-based drug discovery (FBDD), a way to find new drug leads based on screening libraries of low molecular weight fragments of drug-like organic compounds, has become a part of most drug discovery teams’ lead generation strategies and is especially well suited for finding hits against newer types of drug targets such as intracellular protein-protein interactions (PPIs). A few small molecule therapeutics on the market can now trace their origin to fragment-based library screens. However the main challenge remains: growing fragment hits into drug leads. A newer complexity is also facing many discovery groups: how to integrate FBDD hits with those from various drug-lead generation campaigns such as traditional high-throughput screening and newer DNA-encoded library applications. Join biophysical and medicinal chemist colleagues to discuss these questions and more at Cambridge Healthtech Institute's Fragment-Based Drug Discovery conference, now in our 15th year, and the oldest FBDD conference in the industry.

Final Agenda

4月14日(二)

7:00 am Registration Open and Morning Coffee

Fragment Library Design & Screening Approaches

8:00 Welcome Remarks

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

8:05 Chairperson’s Opening Remarks

Maricel Torrent, PhD, Principal Research Scientist, Molecular Modeling, AbbVie

8:10 Fragment Hits and Leads: More than Meets the Eye

Fabrizio GiordanettoFabrizio Giordanetto, PhD, Head, Medicinal Chemistry, D E Shaw Research

An analysis of the molecular and binding properties of fragment hits and leads is presented with special focus on features that these hits and leads tend to have in common, as well as on properties where clear differences occur. Taking account of these preferences in designing and selecting fragments to screen, and in evolving fragments to leads may increase the chances of success in fragment-based drug discovery campaigns.

8:40 Fragment Screening of GPCRs Using NMR

Isabelle KrimmIsabelle Krimm, PhD, Principal Investigator, University of Lyon

G protein-coupled receptors, which constitute the largest family of proteins targeted by approved drugs, still represent a huge opportunity to develop new drugs for “old” targets or orphan receptors. Significant progresses have been made in the field of fragment screening against those challenging membrane proteins. Recent results obtained with the adenosine receptor using NMR and Microscale thermophoresis (from NanoTemper Technologies) will be discussed.

9:10 Biophysics-Based Drug Discovery for Epitranscriptomics

Siegal_GreggGregg Siegal, CEO, ZoBio

Modulation of enzymes that modify RNA (epitranscriptomics) is gaining interest in drug discovery. Gotham Therapeutics and ZoBio are developing inhibitors of METTL3/METTL14, a SAM-dependent methyltransferase that modifies adenosine in mRNA to generate m6A, and thereby regulates protein expression. Here we will present an update on progress.

9:40 Networking Coffee Break

10:05 FEATURED PRESENTATION: Delivering and Exploiting Routine Crystal-Based XChem Fragment Screening

Frank von Delft, PhD, Principal Beamline Scientist, Diamond Light Source and Structural Genomics Consortium; Professor, Structural Chemical Biology, University of Oxford

The dominant problem of fragment approaches remains progressing hits to potency; yet surprisingly, best practice and processes are elusive. With crystal-based screening now routine, including at Diamond’s XChem facility supporting 30-50 campaigns annually, the problem is now acute. We are developing approaches to allow users to routinely progress their high-quality hits to measurable potency, and are exploring Machine Learning approaches to advancing straight to potency.

10:35 Optimization of Fragment Hit Rates: CrystalsFirst’s Proprietary Toolbox

Serghei GlincaSerghei Glinca, PhD, CEO, CrystalsFirst

The application of X-ray crystallography as a primary fragment screening method is widely underutilized due to the limited availability of robust soaking systems and solubility issues of fragments. CrystalsFirst’s SmartSoak® technology, whose origins can be traced to the laboratory of Dr. Gerhard Klebe, is tailored to address those issues. Case studies will be presented demonstrating the advantages of the direct crystallographic screening to identify best possible chemical matter for subsequent FBDD campaigns.

11:05  Fast NMR Structure Determination of Protein-Fragment Complexes

Julien OrtsJulien Orts, PhD, Assistant Professor, Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH

Although the evolution from initial fragment to advanced hit or lead is possible without routine crystallographic support, high resolution structures of the protein–fragment complex greatly facilitate the process. However, it can often be challenging to routinely obtain these crystal structures. In these instances, NMR spectroscopy is the method of choice to guide the medicinal chemistry campaign. We will present our recent development in NMR structure-based drug design for fragments. Case studies will be presented.

11:35 Session Break

11:45 Luncheon Presentation to be Announced

12:30 pm Session Break

Covalent Fragments

1:15 Chairperson’s Remarks

Daniel Erlanson, PhD, Vice President, Chemistry, Frontier Medicines

1:20 How to Be Selectively Promiscuous

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

I will present our approach to the design and discovery of lysine-targeted chemoproteomic probes. Such probes have shown utility in mechanistic cell biology and target engagement experiments.


1:50 Electrophile-Fragment Screening for Rapid Covalent Fragment Probe Screening

#Nir London, PhD, Senior Scientist, Weizmann Institute of Science

Covalent chemical probes and drugs can display unmatched potency, selectivity and duration of action; however, their discovery is challenging. We constructed a library of mildly electrophilic fragments and characterized it by a new high-throughput thiol-reactivity assay. I will present the screening results of this library against a wide array of protein targets. We found selective hits for most targets, and combination with high-throughput crystallography allowed rapid progression in several cases.

2:20 Covalent Fragments Technology for Drug Lead Generation: Past, Present, and Future

Alexander StatsyukAlexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

Covalent fragments is a new lead generation technology, which rests on principles of covalent drug design and fragment-based drug discovery. The main advantage of covalent fragments relative to reversible fragments is that they have enhanced potency and that crystal structures of covalent fragments bound to protein targets can readily be obtained. I will talk about the use of this technology to discover E3 ligase inhibitors and the technology’s future applications in target-based and phenotypic screens.

2:50 Lys- and Tyr-Covalent Ligands: Expanding the Druggable Space for Protein-Protein Interactions Antagonists

Maurizio PellecchiaMaurizio Pellecchia, PhD, Professor, Biomedical Sciences Division, School of Medicine, University of California, Riverside

I will report on several recent studies from the laboratory aimed at deriving derive potent, selective, cell-permeable, and efficacious, protein-protein interactions (PPIs) antagonists by designing agents that can react with lysine, tyrosine, or histidine, given that these are more ubiquitously present at binding interfaces of PPIs compared to cysteine. Examples will include potent and selective Lys- and Tyr-covalent agents targeting various PPIs including IAPs, EphAs, and Bcl-2 proteins.

3:20 Enable Pharma and Biotech Innovation through Open-access Platform

Guo_TaoTao Guo, PhD, Vice President, Head, International Discovery Service Unit, Research Service Division, WuXi AppTec (Shanghai) Co., Ltd.

WuXi AppTec has built a comprehensive drug discovery capability and capacity platform to improve the success of research and shorten the time of development. In this presentation, we will discuss how to use our platform to support Pharma and Biotech drug discovery in ubiquitin-induced protein degradation more quickly and cost-effectively.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

4:35 Plenary Welcome Remarks from Event Director with Poster Finalists Announced

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

Schrodinger

4:45 Plenary Technology Spotlight: Accelerating Drug Discovery from Hit Finding to Candidate Selection with Physics and Machine Learning-Based Calculations

Repasky_MattMatt Repasky, PhD, Vice President, Life Sciences Products, Schrödinger

The impact of the Schödinger computational platform in drug discovery is illustrated using recent case studies from internal and collaborative discovery projects.  The Platform facilitates halving the number of synthesized molecules and time to candidate relative to industry standards.  Key elements of the Platform are described including Free Energy Perturbation to accurately predict relative protein-ligand binding, machine learning to generate and rapidly assess millions of ideas, and collaborative sharing of project information through LiveDesign.

5:10 Plenary Keynote Introduction (Sponsorship Opportunity Available)


5:15 PLENARY KEYNOTE:

Young_WendyMedicinal Chemistry: Where Are We Headed?

Wendy Young, PhD, Senior Vice President, Small Molecule Discovery, Genentech

Major shifts in the way medicinal chemists discover novel medicines have evolved over the past few decades. Technological advances have significantly increased the ability to triage compound design and synthesize compounds faster. New approaches in structural biology have enhanced our ability to visualize molecules and their corresponding binding sites. Drug discovery teams have moved from local to global and our deepened understanding of biology has extended our reach. This lecture will explore past trends in drug discovery, current status of the industry, and the future of medicinal chemistry.

6:00 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

7:00 Close of Day

4月15日(三)

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

In this session, attendees fill their plate from the breakfast buffet and then 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: Orthogonal Biophysical Techniques for FBDD

Moderator: Charles Wartchow, PhD, Senior Investigator, Novartis Institutes for Biomedical Research

  • When to use what: SHG, SPR, NMR, DSF
  • Combining techniques: reconciling data
  • The importance of biochemical assays in biophysical screening campaigns
  • Applications to finding allosteric inhibitors

Topic: Covalent Fragments

Moderator: Daniel Erlanson, PhD, Vice President, Chemistry, Frontier Medicines

  • Reversible vs. irreversible covalent fragments
  • How to characterize covalent fragments
  • Chemistries for cysteine and beyond

Topic: Early-Stage Development of Fragment Hits

Moderator: Martin Scanlon, PhD, Professor, Department of Medicinal Chemistry, Monash University

  • Validation and ranking of hits from primary screens
  • First stages of fragment elaboration (with/without structures)
  • Selection criteria for progression to full chemistry program

Fragment-Based Lead Generation (and Beyond?) Stories

8:30 Chairperson’s Remarks

Mary HarnerMary Harner, PhD, Research Investigator II, Mechanistic Biochemistry, BristolMyers Squibb R&D


8:35 Fragmentology – Fragments of Stories

Rod HubbardRod Hubbard, PhD, Senior Fellow, Vernalis (R&D) Ltd.


Fragments are a mature approach to the discovery of potent, selective hit and lead compounds. In this presentation, I will summarise some new developments and examples taken from various projects including: 1) high-throughput crystallography of crude reaction mixtures to support rapid fragment and hit optimisation; 2) fragment-derived enzyme activators; and 3) using fragments to explore structural determinants of kinase selectivity.

9:05 FBDD Approaches for Diverse Series for Novel Cancer Target, Vps34

Jenny ViklundJenny Viklund, Director, Protein Science & Drug Design, Sprint Biosciences

FBDD approaches were used to create diverse chemical series that inhibit the unexplored cancer target Vps34. Initially, the parameters which are most important for in vivo efficacy (potency, selectivity, PK-profile, tumor permeability, etc) were unknown. Hence, we intentionally selected diverse fragment hits, which were optimized to represent differing profiles for the parameters above. Representative chemical structures will be shared. The in vivo results will be shown in a later presentation at this event.

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

Poster Awards Sponsored by Enamine Ltd

10:30 FEATURED PRESENTATION: Fragment-to-Market Discovery of the pan-FGFR inhibitor BalversaTM (Erdafitinib)

Valerio Berdini, PhD, Director, Computational Chemistry, Astex

FGFR is a family of 4 related receptor tyrosine kinases, each upregulated in several human cancers with high unmet need. This lecture will present the NICR/Astex and Astex/J&J collaboration that lead to the finding of BalversaTM (Erdafitinib): the first inhibitor of FGFR kinases to be approved by FDA and marketed in 2019. From the fragment based screening that identified the early hits, through the medicinal chemistry that progressed them, we will show the criteria leading to the selection of the clinical candidate: a low dose, pan FGFR molecule.

11:00 Fragment Synergies to Deliver Multiple Shots at Moving Targets

Chun-Wa ChungChun-Wa Chung, PhD, Director, Structural & Biophysical Sciences, GlaxoSmithKline, UK


11:30 Design in the Dark – Illuminating the Druggability of 53BP1 with REFiL in the Absence of Structural Data

Beatrice ChiewBeatrice Chiew, Graduate Student, Laboratory of Martin Scanlon, Department of Medicinal Chemistry, Monash University

Structural data is heavily relied on to develop weakly binding fragments into tight binding leads. Unfortunately, structural data is not always available and this can prove to be a roadblock for exciting but difficult targets. We present a target and structure agnostic workflow: REFiL (Rapid Elaboration of Fragment into Leads), which was applied without structural data to the oncology target 53BP1 to expedite the delivery of improved potency leads.

12:00 pm Close of Conference

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

* 活動內容有可能不事先告知作更動及調整。

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