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.
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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 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 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 Inhibition by Destabilization: Allosteric Inhibitors of a Calcium-Dependent Enzyme Identified by Fragment Screening
Mary Harner, Ph.D., Research Investigator, Mechanistic Biochemistry, Bristol-Myers Squibb
Biophysical approaches offer a means to perform fragment screening and mechanistic binding studies orthogonal to more traditional biochemical approaches. NMR spectroscopy and TSA were employed to screen a calcium-dependent enzyme against an in-house fragment library both in the absence and presence of calcium. Mechanistic binding studies using SPR and TSA show calcium-dependence of binding for fragment hits to the target. Despite hits being identified that strongly destabilize the enzyme in the presence of calcium, these hits are potent and allosteric inhibitors of enzyme activity that function through structural disorder and displacement of critical calcium ions.
3:10 Presentation to be Announced
3:40 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Rapid Elaboration of Fragments into Leads (REFIL)
Martin 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 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.
6:15 Close of Day
6:30 Dinner Short Courses*
*Separate registration required.
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Thursday, April 21
7:45 am Breakfast Presentation to be Announced
8:30 PLENARY KEYNOTE PRESENTATION
Gregory 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.
9:30 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 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 Sponsored Presentation (Opportunity Available)
11:30 Combining Biophysical Methods to Improve the Robustness of FBLD
Ben 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.
12:00 pm EXPERT PANEL DISCUSSION: Practical Aspects of Fragment Based Drug Discovery
Moderator: Derek Cole, Ph.D., Director, Chemistry, Takeda
Topics will cover:
- Designing and building fragment libraries
- Screening techniques. Success rates
- Strategies for hit selection
- Fragment optimization
12:30 Luncheon Presentation (Sponsorship Opportunity Available) or 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 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 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 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 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 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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