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

Wednesday, April 20

12:30 pm Registration

FRAGMENT CASE STUDIES

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 Overcoming Platform Biases in Fragment Screening

Mary 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.

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.

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.

Thursday, April 21

7:45 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.

9:30 Coffee Break in the Exhibit Hall with Poster Viewing

BEST PRACTICES FOR FRAGMENT-BASED DRUG DESIGN AND SCREENING

10:10 Chairperson’s Remarks

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

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 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

NEW APPROACHES

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

The newer, synthetic macrocyclic and constrained peptide compounds (ranging in size from .5 -2 kilodaltons) offer the promise of being the ‘ideal’ class of compounds for new drug entities. Their cyclical shape enables solubility and stability affording them the possibility to be developed into oral medications and most are small enough to cross the cell membrane to reach intracellular targets, where many of the causes and solutions to diseases reside. And because of macrocyclics’ slightly larger size than typical small molecules, they offer more specificity and have greater chances of disrupting protein-protein interactions. However, theory has yet to be fully realized. Solubility and cell permeability issues are still being addressed. This meeting will focus on the remaining challenges, cover the new targets being addressed with macrocyclics and provide updates on a few early examples of compounds advancing in drug development.

Final Agenda

Day 1 | Day 2 | Download Brochure

Wednesday, April 20

12:30 pm Registration

DESIGN CONSIDERATIONS AND CHALLENGES FOR MACROCYCLICS

1:30 Chairperson’s Remarks

Scott Lokey, Ph.D., Professor, Chemistry and Biochemistry, University of California, Santa Cruz

2:10 Passive Membrane Permeability in Cyclic Peptides: New Rules for a New Chemical Space

Scott Lokey, Ph.D., Professor, Chemistry and Biochemistry, University of California, Santa Cruz

The prospect that macrocyclic peptides that lie well outside the Rule of 5 can have drug-like, passive cell permeability has stimulated much effort toward understanding the physical basis for the behavior of such outliers. I will discuss our latest results from a series of systematic studies using a variety of synthetic, biophysical, and analytical tools, designed to probe the specific structural and physicochemical constraints that govern ADME behavior in macrocycles in the MW~1000 range.

2:40 Computational and Physical Properties of Orally Bioavailable Cyclic Peptides

Alan M. Mathiowetz, Ph.D., Director, Pfizer Worldwide Medicinal Chemistry – Cardiovascular and Metabolic Diseases

An increasing number of orally bioavailable cyclic peptides have been discovered in recent years, providing us with an opportunity to identify the design principles for achieving improved permeability in this traditionally challenging physical property space. A variety of computational parameters and measured physical properties will be discussed, describing their relationship to permeability and other ADME properties – both across a broad dataset of compounds and for specific published orally bioavailable peptides.

3:10 Technologies Enabling Macrocycle Design

Dan Sindhikara, Ph.D., Senior Scientist, Schrödinger

Macrocycles can offer attractive properties such as defiance of Ro5 guidelines while posing new challenges due to their unique topology. Combining state-of-the-art modelling software with bleeding-edge macrocycle-specific technology, we are paving the way to rational macrocycle design. Our tools focus on our new high-speed, accurate macrocycle sampling algorithm able to rigorously sample macrocycles within seconds to minutes. Leveraging the macrocycle sampling protocol, we can now quickly do physics-based passive-permeability predictions, docking, and binding free energy calculations. Further we are developing technology to quickly generate virtual macrocycle libraries for screening containing millions of compounds or more.

3:40 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Computer-Aided Macrocycle Design

Matthew Jacobson, Ph.D., Professor, Pharmaceutical Chemistry, University of California, San Francisco

I will discuss the central challenge in computational modeling of macrocycles—predicting the three-dimensional structure of the backbone—with applications to permeability prediction; structure-based or ligand-based design; and the creation of virtual libraries. Examples will include cyclic peptides, polyketides, and other classes of natural product and synthetic macrocycles.

5:00 From Haystack to Needle: Using Encoded Libraries at GSK

Christopher Phelps, Ph.D., Manager, Drug Design & Selection Boston, RD Platform Technology & Science, GSK

In 2005 scientists at Praecis Pharmaceuticals first realized the power of DNA encoded libraries with successful selections of triazine scaffolds against p38 kinase. A year later, the same team screened four targets from GSK, and the outcome of that collaboration was the acquisition of Praecis and the first integration of encoded library technology (ELT) into the hit ID engine of a major pharmaceutical company. This presentation will review some milestones of that journey and the technical advances in library chemistry, selection methods, and informatics that were enabled within GSK.

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.

Thursday, April 21

7:45 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.

8:00 Morning Coffee

9:30 Coffee Break in the Exhibit Hall with Poster Viewing

MACROCYCLIC SYNTHESIS AND SCREENING

10:10 Chairperson’s Remarks

Dehua Pei, Ph.D., Professor, Department of Chemistry and Biochemistry, The Ohio State University

10:15 Synthesis and Screening of Vast Libraries of DNA-Encoded Macrocycles

Thomas Kodadek, Ph.D., Professor, Chemistry and Cancer Biology, The Scripps Research Institute, Scripps Florida

Macrocycles that mimic some of the favorable properties of natural products are of great interest as chemical probes and drug leads. As a potentially rich source of such compounds, we have created vast DNA-encoded combinatorial libraries of structurally complex macrocycles displayed on 10 µm beads. These libraries can be screened by incubation with fluorescently labeled target proteins and unlabeled competitor proteins and hits can be isolated using a flow cytometer. This system constitutes a powerful tool for the discovery of bioactive macrocycles as well as a method for assessing the relative merits of macrocycles and linear molecules as protein ligands.

10:45 Step-Wise Selection of Peptide Binders Using High-Density Peptide Arrays

Jigar Patel, Ph.D., Director, Technology Innovation, Roche NimbleGen Inc.

We will describe a step-wise selection method using L and D amino acids synthesized on High Density Peptide arrays using Streptavidin as a case example. We have identified various binding peptides, and have determined their co-crystal structures. All studied peptides were found to bind to the same biotin-binding pocket of streptavidin and pre-incubation of streptavidin with biotin completely abolishes any of the peptide binding. Discovery of multiple peptides in both linear and cyclic forms with different sequences bound to the biotin site suggests that these peptides can demonstrate a significant plasticity in creating specific contacts with the same target.

11:15 Moving Macrocyclic Research Forward: New Rules and Drug Discovery Application

Roman Kombarov, Ph.D., Head, Business Development, ASINEX Corporation

Over the past 6 years, we have synthesized over 30,000 macrocyclic compounds and optimized synthetic techniques with special focus on reaction types used for scaffold synthesis. This talk will relate lessons learned and stress two main directions in our macrocyclic research: the first is to refine a set of rules for cellular permeability and the second involves drug discovery application of macrocyclic chemistry with a special focus on the areas of oncology and anti-bacterial research.

11:45 Joining Chemistry and Biology to Make Macrocycles

James H. Naismith, Ph.D., Professor, Chemical Biology, St. Andrews University

I will report our progress on combining enzymes, some of which have re-engineered, from the patellamide and patellamide-like pathways with organic chemical synthesis. Our objective is access novel peptide/non-peptide hybrid macrocyclic compounds that would otherwise be very challenging to make. These compounds are being designed as novel inhibitor starting points as they can encode particular epitopes in a conformationally tuneable scaffold. I will also report work on combining solid phase synthesis with the enzymes.


12:15 pm Conformational Sampling of Macrocycles: Recent Progress
Paul Hawkins, Ph.D., Head, Scientific Solutions, OpenEye Scientific Software
Macrocyclic molecules have been shown to be orally bioavailable ligands for targets such as GPCRs and protein-protein interfaces. Greater exploitation of macrocycles in drug discovery has been stymied by a lack of computational methods to investigate their properties, including their conformational space. Here we present some recent work on conformational sampling of macrocycles that attempts to balance sampling near conformations likely to be relevant to biological activity with the time required for the calculation.

12:45 Luncheon Presentation (Opportunity Available)

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

CASE STUDIES: COMPOUNDS IN EARLY DEVELOPMENT

2:15 Chairperson’s Remarks

Eric Marsault, Ph.D., Professor, Medicinal Chemistry and Pharmacology, University of Sherbrooke

2:20 Lorlatinib (PF-06463922), a Macrocyclic ALK/ROS1 Inhibitor for the Treatment of Resistance Mutations and Brain Metastasis

Ted W. Johnson, Ph.D., Senior Principal Scientist, Oncology Chemistry, Pfizer San Diego

PF-06463922, a novel macrocyclic inhibitor of ALK/ROS1 currently in Phase I/II clinical trials, demonstrated low nanomolar inhibitory activity against a panel of ALK kinase domain mutations with overlapping CNS activity to treat brain metastasis. Structure-based drug design, CNS drug design and efficacy data will be presented.

2:50 Cyclohexylgriselimycin: A Synthetic and New Anti-Tuberculosis Drug Candidate

Evelyne Fontaine, Ph.D., Laboratory Head, Infectious Diseases, Medicinal Chemistry, Sanofi

We present a case study in peptide chemistry: from a poorly drug-like parent compound, the natural cyclodepsipeptide Griselimycin discovered 50 years ago, we’ll report how we solved the metabolic lability, improved the oral PK and balanced the antibacterial potency with lipophylicity and solubility. Total synthesis including SPPS and macrocyclisation was used to prepare more than 230 cyclodepsipeptides, and also 200G of cyclohexylgriselimycin. NMR 3D structure of Cyclohexylgriselimycin, RX-structure in complex with DnaN and MOA elucidation will be presented.

3:20 Refreshment Break

3:40 Macrocycle Design for PD1-PD1L and p53-MDM2

Alexander Dömling, Ph.D., Professor, Drug Design, University of Groningen

Protein protein interactions are a key target area for macrocycles due to their often difficult druggability by classical approaches such as small molecules. MDM2-p53 for examples comprise a well-structured interface with 700A2 buried interface while PD1-PD1L is very flat and featureless comprising 2000A2 buried interface. Here we report the design and synthesis of PD1-PD1L and p53-MDM2 directed macrocycles including their protein complexes. PD1-PD1L is a game changing target in immuno-oncology.

4:10 Orally Stable GI restricted Peptides for InflammatoryBowel Diseases

Greg Bourne, Ph.D., Senior Research Fellow, Chemistry, Protagonist Therapeutics

Inflammatory bowel disease (IBD) offers clinically validated targets for gut restricted drug development. Protagonist has applied its technology platform and expertise in peptide and medicinal chemistry to develop novel, potent, target specific and orally stable gut restricted peptides for α4β7 integrin and IL23-receptor. These peptides have minimal /no systemic exposure, yet are active in preclinical IBD models. We will discuss strategies in developing these orally stable peptide antagonists for GI restricted diseases.

4:40 Macrocyclic Drug Candidates for Lung Diseases andNovel Antibiotics

Daniel Obrecht, Ph.D., CSO, Pharmaceutical Research, Polyphor Ltd.

We have established two complementary, fully proprietary macrocycle technologies that yield synthetically accessible compounds that are amenable to a rapid and efficient optimization process, and have a proven potential to provide innovative drug candidates for complex target classes. I present two case studies: POL6014 in Phase I development for cystic fibrosis and other rare lung diseases, is a highly potent and selective macrocyclic inhibitor of human neutrophil elastase (HNE) and POL7080, a novel breakthrough antibiotic against Gram-negative bacteria.

5:10 Close of Conference

Day 1 | Day 2 | Download Brochure