11th Annual

Fragment-Based Drug Discovery

From Hits to Leads and Lessons Learned

April 20-21, 2016

Fragment-Based Drug Discovery icon  

Fragment-based drug discovery (FBDD) is an approach for finding new drug leads that over the past decade has increasingly been adopted by research departments at biotechnology and pharmaceutical companies. However, rarely is FBDD the only funnel for providing small molecule lead compounds and often medicinal chemists are faced with the challenge of using information from high-throughput as well as other efforts to optimize and develop compounds with the best drug potential. But with more than thirty compounds in clinical trials and at least one drug on the market whose origins can be traced to fragment-based approaches, there is a wealth of experience and information to be shared for moving the field forward. Join fellow biophysical and medicinal chemists to discuss and debate pitfalls, solutions and best practices in this growing area of drug discovery.

Final Agenda

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Wednesday, April 20

12:30 pm Registration


1:30 Chairperson’s Remarks

Daniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.

1:40 Fragment-Screening Antibacterial Targets Using Surface Plasmon Resonance Methods

Adam_RensloAdam Renslo, Ph.D., Associate Professor, Department of Pharmaceutical Chemistry, University of California San Francisco

The emergence of expanded-spectrum beta-lactamases (ESBLs) and carbapenemases in Gm-negative pathogens threatens the future effectiveness of important classes of antibiotics. Our group has been applying fragment screening and structure-guided medicinal chemistry to identify novel, non-covalent inhibitors of clinically relevant beta-lactamases. In this talk we will describe computational and SPR methods for fragment screening of ESBLs and carbapenemases.

2:10 Fragment-Based Discovery of Novel MAP4K4 Inhibitors: Tales of Two Fragments

Huifen_ChenHuifen Chen, Ph.D., Senior Scientist, Discovery Chemistry, Genentech

MAP4K4 is a serine/threonine protein kinase implicated in the regulation of many key biological processes including cell migration, adhesion, invasion and neuronal degeneration. To study its function in various disease contexts, we embarked on an endeavor to identify potent and selective MAP4K4 inhibitors using fragment-based drug discovery approach. Herein I will present the identification and optimization of two fragments and the distinct profiles of two classes of highly potent MAP4K4 inhibitors. One of the classes demonstrated excellent potency and selectivity, and was further optimized to yield a novel biological tool compound (GNE-495) with efficacy in retinal angiogenesis model.

2:40 Overcoming Platform Biases in Fragment Screening

Mary_HarnerMary Harner, Ph.D., Research Investigator, Mechanistic Biochemistry, Bristol-Myers Squibb

Fragment screening is now widely accepted as a complementary screening paradigm to HTS for identifying novel chemical moieties leading to target modulation.  The chemical simplicity of fragments typically results in the initial positives of a screen having low potency; activities are often near mM concentrations.  To detect these weaker compounds, biophysical assays have become the norm, with the 2 most widely used techniques being SPR and NMR.  A comparison of various methods for fragment identification reveals that orthogonal methods for fragment detection frequently yield surprisingly low overlap of resultant hit lists. This presentation will describe our efforts to understand this apparent disconnect between assays, and suggest ways to focus subsequent resources on the most promising compounds.
GE Healthcare Logo

3:10 Sense and Sensitivity: Screening and Characterisation of Fragment Binders Against WT GPCR Drug Targets using Highly Sensitive Biacore S200

Paul Belcher, Ph.D., Functional Leader, Biacore™ GE Healthcare

G protein coupled receptors (GPCRs) are the targets of 30-40% of all approved drugs. However many approaches successfully applied to drug discovery for soluble protein targets have made a limited impact on GPCR’s due to challenges in obtaining pure, active, membrane free receptors for structural and biophysical investigation. In recent years biophysical techniques in combination with improvements in protein engineering and handling have advanced to face the challenges of studying membrane bound GPCR’s with SPR in particular becoming increasingly utilized in the study of GPCR’s as the sensitivity of the detections systems has improved. Here we present the results from a collaboration with the Hopkins-Navratilova lab at the University of Dundee highlighting the importance of instrument sensitivity characterizing GPCR’s with the Biacore™ S200.

Aptuit3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Rapid Elaboration of Fragments into Leads (REFIL)

Martin_ScanlonMartin Scanlon, Ph.D., Associate Professor, Medicinal Chemistry, Monash Institute for Pharmaceutical Sciences

Fragments that emerge from primary screens often have low affinities with KD values in the high μM to mM ranges. Therefore a significant challenge for FBLD is to develop these initial fragments into more potent ligands. In this presentation I will describe a strategy that we have implemented to enable weakly-binding fragment hits to be elaborated into more potent ligands.

5:00 Fragment-Based Discovery of Chemical Probes for BRD9

Jark_BottcherJark Böttcher, Ph.D., Distinguished Scientist, Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG

Three parallel biophysical methods were used to screen our proprietary fragment library against the BRD9 bromodomain (differential scanning fluorimetry (DSF), surface plasmon resonance (SPR) and microscale thermophoresis (MST). Structure guided chemical optimization of the initial hits resulted in the chemical probes, that should prove useful in further probing BRD9 bromodomain biology in both in vitro and in vivo settings.

5:30 Breakout Discussions

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. Check our website in February to see the full listing of breakout topics and moderators.

Topic: Structuring Academic/Industry Partnerships

Adam Renslo, Ph.D., Associate Professor, Department of Pharmaceutical Chemistry, University of California San Francisco
Chris Smith, Ph.D., Director, Medicinal Chemistry, COI Pharmaceuticals

  • Direct Licensing Deals
  • Lab to Lab collaborations with shared publications
  • Sharing of/paying for use of resources
  • Using a third party or venture capital company (COI's example)

Topic: Making Sense of Conflicting Data

Ben Davis, Ph.D., Research Fellow, Biology, Vernalis Research
Matthew Marx, Ph.D., Senior Director, Head of Drug Discovery, Mirati Therapeutics

  • What to do when techniques don't agree
  • Artefacts, pitfalls and reliability
  • Knowing the limitations

Topic: ‘Starting a Start-Up’

Moderator: Iwan de Esch, Ph.D., Professor, Medicinal Chemistry, VU University Amsterdam & Griffin Discoveries BV

  • What to do first?
  • Things I wish I had known
  • How many people to start with?

6:15 Close of Day

6:30 Dinner Short Courses*

*Separate registration required.

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Thursday, April 21

Hitgen7:45 am Breakfast Presentation: DNA Encoded Libraries and the Economics of Early Stage Drug Discovery: Managing the Economics of Serendipity

Barry A. Morgan, Ph.D., Visiting Professor, Institute for Molecular Medicine, University of Texas Health Sciences

A review of FDA approved drugs, and the increased cost of drug discovery over the past few decades highlights the unsustainability of the current model for bringing new medicines to clinical practice. We will review the factors involved in this analysis, and present a case for DNA encoded library technology bringing disruptive change to early stage drug discovery.


Cell-Penetrating Miniproteins

Gregory VerdineGregory L. Verdine, Ph.D., Professor, Departments of Stem Cell and Regenerative Biology, Chemistry and Chemical Biology, and Molecular and Cellular Biology, Harvard University

It has been estimated that as few as 10-15% of all potential targets are targetable in vivo by either biological or small molecules. To address this deficiency, we and FOG Pharmaceuticals are developing cell-penetrating mini-proteins, molecules that combine the ability of proteins to target large flat surfaces, with the ability of small molecules to penetrate cells. Progress on the development of cell-penetrating mini-proteins will be reviewed in this talk.

Advanced Cellular Dynamics9:30 Coffee Break in the Exhibit Hall with Poster Viewing



10:10 Chairperson’s Remarks

Derek Cole, Ph.D., Director, Chemistry, Takeda

10:15 FEATURED PRESENTATION: Peptidyl Prolyl Isomerase and Fragment Strategies: The Route from Millimolar to Nanomolar

Matthias_FrechMatthias Frech, Ph.D., Director, Molecular Interactions & Biophysics,EMD Serono

The substrate binding site of peptidyl prolyl isomerases is in a difficult location for identifying inhibitory molecules against. Besides high throughput screening and computational methods, we set up a fragment approach to identify additional hit matter. Low affinity fragments were identified as starting points. We used different optimization strategies so the initial hit matter could be improved to chemical scaffolds with high affinity and activity.

10:45 FBDD Infrastructure at Takeda

Xiaolun Wang, Ph.D., Senior Scientist, Medicinal Chemistry, Takeda San Diego

Fragment Based Drug Discovery (FBDD) has established itself as a viable and productive approach to lead generation and the optimization of novel small molecule drugs. This presentation will describe how Takeda built its FBDD capabilities including the design and characterization of chemically diverse fragment libraries, the implement of different biophysical screening technologies, and the demonstration of our FBDD effort with a case study.

11:15 Combining Biophysical Methods to Improve the Robustness of FBLD

Ben_DavisBen Davis, Ph.D., Research Fellow, Biology, Vernalis Research

A wide range of techniques is used to detect and characterise the low affinity interactions which typify FBLD. Each of these techniques has distinctive sensitivities and requirements, and this can lead to variations in the output from different assays. However, careful examination and combination of these results can improve the robustness and quality of an FBLD campaign. I will discuss a variety of recent examples of fragment screening and validation to illustrate this approach.

11:45 pm EXPERT PANEL DISCUSSION: Practical Aspects of Fragment Based Drug Discovery

Moderator: Derek Cole, Ph.D., Director, Chemistry, Takeda

Panelists: Huifen Chen, Ph.D., Senior Scientist, Discovery Chemistry, Genentech; Daniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.; Matthias Frech, Ph.D., Director, Molecular Interactions & Biophysics,EMD Serono; Martin Scanlon, Ph.D., Associate Professor, Medicinal Chemistry, Monash Institute for Pharmaceutical Sciences

Topics will cover:

  • Designing and building fragment libraries
  • Screening techniques. Success rates
  • Strategies for hit selection
  • Fragment optimization

12:30 Enjoy Lunch on Your Own

1:30 Ice Cream Refreshment Break in the Exhibit Hallwith Poster Awards


2:15 Chairperson’s Remarks

Matthew Marx, Ph.D., Senior Director, Head of Drug Discovery, Mirati Therapeutics

2:20 Protein-Observed Fluorine NMR for Fragment Screening

William_PomerantzWilliam Pomerantz, Ph.D., Assistant Professor, Department of Chemistry, University of Minnesota

To facilitate early lead discovery, we describe a rapid, protein-based 19F NMR method for fragment screening. We report on testing the sensitivity, accuracy, and speed of this method from a small molecule screen with the protein interaction domain of CBP, KIX. We have extended our method to screening against bromodomains Brd4, BrdT and BPTF. The speed, ease of interpretation,and low concentration of protein needed for binding experiments affords a new method to discover leads in fragment screens.

2:50 A Fully Automated Pipeline for Fragment-Based Screening through Macromolecular Crystallography

Jose_MarquezJose A. Marquez, Ph.D., Team Leader, Head of Crystallization Facility, Grenoble Outstation, European Molecular Biology Laboratory (EMBL) Grenoble Outstation

Macromolecular crystallography is a powerful tool in drug design and in particular in the context of fragment-based approaches. However, manual crystal handling makes it a manpower intensive application limiting the size of the libraries that can be analyzed as compared to other biophysical approaches. We present the fully automated system we have developed for crystal soaking, mounting and cryocooling (CrystalDirect), which is currently in operation at the High Throughput Crystallization laboratory of the EMBL Grenoble outstation.

3:20 Refreshment Break

3:40 A New Approach for Quality-Control Screening of Fragment Libraries

Yutao_JiangYutao Jiang, MS, Senior Research Associate, Medicinal Chemistry, Genentech

We introduce a novel high throughput LCMS/UV/CAD/CLND system by increasing both the quantitation accuracy and the range of compounds amenable to testing, in particular, low molecular weight “fragment” compounds. Our results show that the addition of CAD and CLND to LCMS/UV is more reliable for concentration determination for a wider range of compounds than either detector alone without significantly increasing run time per sample.

4:10 X-Ray and Activity Fragment Screening across Subfamilies of Lysine Demethylases and Ribosomal Hydroxylases for Active-Site Characterization

Radek_NowakRadek Nowak, Ph.D., Research Associate, Structural Genomics Consortium, University of Oxford

We combined X-ray based fragment screening with inhibitor data for several subfamilies of human oxoglutarate dependent oxygenases to prioritize fragments for further lead development. We developed an X-ray fragment screening platform with JARID1B and JMJD2D and obtained crystal structures for selected fragments showing diverse active site metal binding modes. The fragments occupied different parts of the active site pockets including putative allosteric sites, non-metal binding active sites and metal chelator sites. These starting points can be used to rationalize ligand binding hotspots for various subfamilies for further development of selective chemical tools for this epigenetic enzyme family.

4:40 Fragment-Based Drug Discovery with Dual-Display DNA-Encoded Chemical Libraries

Joerg_ScheuermannJoerg Scheuermann, Ph.D., Senior Scientist, Chemistry and Applied Biosciences, ETH Zurich

We describe our development of DNA-encoded chemical libraries (DECLs), which are increasingly considered for hit identification. While single-pharmacophore DECLs typically display drug-like compounds on one DNA strand, dual-pharmacophore feature the simultaneous display of fragments on both DNA strands, which allows for the identification of synergistically binding pairs of fragments. We will report on the use of both types of DECLs for the identification of hits against “difficult” protein targets.

5:10 Close of Conference

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