Fragment-Based Drug Discovery
From Hits to Leads and Lessons Learned
April 25-26, 2017 | Sheraton San Diego Hotel & Marina
Fragment-based drug discovery (FBDD) approaches are now common in lead generation. Two compounds originating from fragment-based campaigns have made it all the way to market and at least thirty fragment-derived drug candidates are in clinical trials. The oldest fragment-focused annual conference in the field, this meeting will continue to enable FBDD practitioners to share best practices and learn from one another. Evolving thoughts on qualities of a good library, advances in screening techniques, and the challenges of transforming fragments to leads will all be part of the agenda.
Scientific Advisor: Daniel A.Erlanson, Ph.D., Co-Founder,CarmotTherapeutics, Inc.
Tuesday, April 25
12:30 pm Registration
1:30 Chairperson’s Remarks
Daniel A. Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.
1:40 Late-Breaking Presentation:Expanding the Ligandable Proteome: Ligand and Target Discovery by Fragment-Based Screening in Human Cells
Christopher Parker, Ph.D., Postdoctoral Fellow of the American Cancer Society, Cravatt Lab, Department of Chemical Physiology, The Scripps Research Institute
We developed a platform that integrates fragment-based ligand discovery with quantitative chemical proteomics to map thousands of reversible fragment-protein interactions directly in human cells. Many interactions can be site-specifically determined and involve proteins that fall outside of traditional druggable classes. We advance this knowledge to create ligands that affect protein activity and to identify by phenotypic screening ligand-protein interactions that regulate complex cellular processes.
2:10 Advancing a Clinical Candidate Targeting IRAK4 from a Fragment Lead
Seungil Han, Ph.D., Associate Research Fellow, Structural Biology & Biophysics, WorldWide Research & Development, Pfizer, Inc.
Small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) are being developed for the treatment of SLE and RA. An integrated approach that included structural, biochemical, computational and medicinal chemistry disciplines has enabled us to develop a first-in-class, highly ligand efficient and kinome-selective IRAK4 clinical compound starting from a weak fragment.
2:40 Targeting Inducible Nitric Oxide Synthase (iNOS)
Fredrik Edfeldt, Ph.D., Associate Principal Scientist, Biophysics, Discovery Sciences, AstraZeneca R&D, Sweden
In this case study we describe the discovery of two novel series of iNOS inhibitors. Initial NMR screening yielded a set of fairly potent starting points. We established a soakable crystal system that allowed us to determine X-ray structures with 10 fragment hits. In subsequent chemistry efforts we made rapid progress: for the two series only six key crystal structures were determined and only ~50 compounds synthesized in order to reach low nanomolar cell potency.
3:10 Comparative Fragment Screening Approaches for ClpP Activators
Aman Singh, Ph.D., Post Doc Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital
Caseinolytic protease P (ClpP) represents an important emerging target for the treatment of chronic bacterial infections (Conlon et al, 2013). Antibiotic acyldepsipeptides (ADEPs) specifically target ClpP allosteric activation domain by relieving regulatory input of ATPase chaperons ClpX/ClpC, resulting in deregulated activation of ClpP and self-digestion. However, the ADEPs have poor pharmacological properties and we are seeking the discovery of novel non-peptidic ClpP activators. For this purpose a suite of computational, biochemical and biophysical screening approaches have been developed. Herein we will present the results of our fragment screening efforts of our library of 5000 compounds against S. aureus ClpP. The hit rates of Protein Thermal Shift, Fluorescence Polarization, Surface Plasmon Resonance ClpP screening assays will be compared in regard to successful identification of biochemical activators and lead progression. Results of this study have identified multiple validated hits, producing X co-crystal structures and one series that has been chemically built out to obtain activators with low micromolar potency . This presentation will conclude with a retrospective analysis of the success of various screening approaches against this complex protein-protein interaction site target.
3:40 Refreshment Break in the Exhibit Hall with Poster Viewing
4:30 Fragment-Based, Structure-Enabled Approach to the Discovery of Novel Inhibitors of the BET Family of Proteins: ABBV-075 and Others
Le Wang, Ph.D., Principal Research Scientist, Oncology Discovery, Chemistry, AbbVie
Phenotypic cell-based screening assays combined with affinity chromatography and mass-spectrometry identified the BET family of bromodomains as a potential target for blocking proliferation in a variety of cancer cell lines. A 2-dimensional NMR fragment screen was conducted in order to search for novel scaffolds. Protein X-ray co-crystal structures of five NMR fragment screen hits were solved. This is a successful medicinal chemistry story starting from a weak NMR screen fragment to ABBV-075, our clinical candidate.
5:00 A Platform for Development of Combinatorial Inhibitory Chemotypes: A Potent Inhibitor of PI3K, BRD4 and CDK4/6 (SRX-3177) in One Small Molecule
Donald Durden, M.D., Professor, Department of Pediatrics, UCSD
A novel thienopyranone molecular scaffold has been discovered and modeled in silico to develop chemotypes which selectively inhibit PI3 kinase, the bromodomain protein BRD4 and CDK4/6. Molecular modeling studies and a robust PI-3K, CDK6 and BRD4 BD1 homology model have been developed and will be presented to describe how these single small molecules can bind to inhibit such distinctly different proteins and their functions.
5:30 Breakout Discussions
Breakout Discussions (we are pioneering a new format in this track that is different from concurrent tracks):
Participants will be divided into three groups. After everyone briefly introduces him/herself to the group (name, place of work), discussion will commence on two or three specific topics. Suggested topics are below but we may also try to solicit and vote-on topics during the conference. After spending approximately 5-7 minutes/topic, the moderator from each group will give a 2-minute report-back to the larger audience and then the next topic will be discussed.
Discussion Topics for all Moderated Groups:
- High content or phenotypic screens with fragments: who has done what, how was it done, what does the future look like in this space?
- -X-ray crystallography as primary screen: pros/cons
- Using fragments for difficult targets -- examples -- and is this a good approach?
Group 1: Derek Cole, Ph.D., Director, Medicinal Chemistry, Takeda
Group 2: Rod Hubbard, Ph.D., Professor, University of York and Senior Fellow, Vernalis Research
Group 3: Dominic Tisi, Ph.D., Associate Director, Molecular Science, Astex
6:15 Close of Day
6:30 Dinner Short Courses*
*Separate registration required
Wednesday, April 26
7:45am Plenary Breakfast Presentation: NMR in Fragment-Based Lead Discovery (FBLD)
Stefan Jehle, Ph.D., Product Manager, Bruker BioSpin
NMR is ideally suited for detecting low affinity fragments in solution for FBLD and allows quality control of the screening library on the fly. The large dynamic range with respect to the MW of the target and binding affinities enables its application to a broad range of targets. During this presentation, we will show straight forward NMR methods in FBLD for non-experts, basic principles, data acquisition, data analysis, automation options, software solutions and assay development.
8:30 PLENARY KEYNOTE PRESENTATION
Drug Discovery and Pan-Assay Interference Compounds (PAINS)
Jonathan B. Baell, Ph.D., Professor, Medicinal Chemistry, Monash University
I will discuss issues around the PAINS filter that we published in 2010 and since then has generated much discussion in the industry. The PAINS filter helped explain the difficulties with certain compounds that many hit-to-lead medicinal chemists around the world, principally in academia and small biotechs but to some extent in big pharma also, were encountering. However, because some known drugs contain PAINS, there is the fear that such filters may be too stringent.
9:30 Coffee Break in the Exhibit Hall with Poster Viewing
10:40 Chairperson’s Remarks
Mary Harner, Ph.D., Research Investigator II, Leads Discovery & Optimization, Bristol-Myers Squibb
10:45 FBDD: Part of an Integrated Drug Discovery Platform
Derek Cole, Ph.D., Director, Medicinal Chemistry, Takeda
11:15 Fragment-Based Screening Using X-ray Crystallography: Challenges and Practical Considerations
Dominic Tisi, Ph.D., Associate Director, Molecular Science, Astex
This presentation will focus on the key challenges associated with successful prosecution of a fragment screen. I will discuss the practical hurdles associated with protein characterisation and crystallographic fragment screening and how biophysical methods can be synergistically employed during a screen. Case studies will be given which highlight the challenges and rewards of using crystallography as a primary screening method for fragment based lead generation.
11:45The M(u)ST Use Approach for Fragment Screening
Tom Mander, Ph.D., MBA, COO, Domainex
MicroScale Thermophoresis (MST) is a relatively new technology for detecting and quantifying binding of ligands to target proteins. Domainex has used MST to screen fragment libraries and thereby enable its fragment-based drug design platform. This approach will be illustrated with a case study on the lysine methyltransferase, G9a.
12:00 pm Discovering Drug Seeds by Practical NMR Strategies
Steven LaPlante, Ph.D., Professor, Innovative Drug Discovery, University of Quebec INRS-IAF and NMX
This presentation will describe the critical role NMR is playing for discovering the seeds for new drugs. Central to these efforts is the creation of a new curated fragment library, the development of consensus NMR screening methods, the design of new NMR software, and the application of follow-up NMR experiments. As a result, quality hits are prioritized which significantly benefits medicinal chemistry efforts.
12:30 Luncheon Presentation: An Optimized, Integrated Workflow for FBLD
Gregg Siegal, Select CEO, ZoBio
Over the past 12 years, ZoBio has built an integrated technology pipeline that enables a wide array of targets for FBLD and maximizes the chance of successfully generating high quality leads. This talk will provide an overview of our high throughput protein engineering, orthogonal fragment screening and NMR plus X-ray structural biology capabilities and how we tailor projects to our clients needs.
1:30 Dessert Break in the Exhibit Hall with Poster Awards
2:15 Chairperson’s Remarks
Seth Cohen, Ph.D., Professor, Department of Chemistry and Biochemistry, University of California, San Diego
2:20 Important Aspects of Fragment Screening Collection Design
Ashley Adams, Ph.D., Senior Scientist, Discovery Chemistry and Technology, AbbVie, Inc.
Recently, AbbVie embarked on an initiative to completely revamp our fragment screening collection. Our initial fragment deck predated Ro3 dogma with little attention paid to the physicochemical properties of the collection and thus contained a significant number of intractable starting points for fragment optimization campaigns. This presentation highlights the important design criteria and analyses that formed the basis of this important exercise.
2:50 Natural Products: Promising Starting Points for Fragment-Based Screening
Tim Schuhmann, Ph.D., Investigator III, Natural Products Unit, Novartis Pharma AG
We generated a library of natural-product inspired fragments largely by chemical degradation of complex natural products. As shown by computational analysis, the resulting set is nicely complementing classical fragment screening sets by adding spherical motives and shows promising biological activities in the screens performed so far. In the talk, our strategy, the generation and implementation of the set as well as preliminary biological data and follow-up approaches will be presented.
3:20 Retrospective Analysis of Validated Fragment Hits Bound to Their Targets
Fabrizio Giordanetto, Ph.D., Head, Medicinal Chemistry, D. E. Shaw Research LLC
This is a first of its kind retrospective analysis of a large set of validated fragment hits bound to their corresponding targets to reveal preferred molecular properties, topologies and interacting motifs at a fragment level across a large variety of protein targets. It will inspire expert medicinal and computational chemists, as well as provide an important fragment evaluation primer to non-experts.
3:50 Refreshment Break
4:20 FEATURED PRESENTATION: Probing GPCR and Bacterial Targets with Fragment Based Discovery
Rod Hubbard, Ph.D., Professor, University of York and Senior Fellow, Vernalis Research
I will summarize two current research projects: (1) Screening of the molecular machine that is the bacterial replisome, identifying fragments that disrupt DNA replication and beginning to identify which targets/interfaces are effected; (2) In collaboration with groups in Zurich and Melbourne, NMR fragment screening of stabilized GPCRs by Vernalis with some cellular activity readouts. These projects illustrate the power of fragments in chemical biology – using chemical tools to explore biological systems.
4:50 FBDD for Metalloenzyme Inhibition – A Bioinorganic Perspective
Seth Cohen, Ph.D., Professor, Department of Chemistry and Biochemistry, University of California, San Diego
This presentation will discuss a bioinorganic approach to fragment-based drug discovery (FBDD) that will focus on the use of this method for developing metalloenzyme inhibitors. FBDD is found to be a very effective and advantageous strategy for drugging metalloenzymes and this presentation will highlight some case studies spanning anti-cancer, viral, and bacterial targets. Some fundamental studies, including structural investigation of fragments and studies to address the selectivity of metalloenzyme inhibitors, will be discussed.
5:20 Fragment Docking Identifies Inhibitors for Jumonji Histone Demethylases 4 Subfamily
Magdalena Korczynska, Ph.D., Associate Specialist, Brian Shoichet Lab, Department of Pharmaceutical Chemistry, University of California San Francisco
Using crystal structures of the KDM4 subfamily we have performed virtual screening of a purchasable in silico fragment library. This screen identified 7 inhibitors with IC50 values between 18μM and 176μM (ligand efficiencies of >0.3). Molecules containing the 5-aminosalicylate core were selected as candidates for further optimization. After several rounds of iterative target-specific compound docking, hybrid molecule design, compound synthesis, in vitro characterization, and crystallization, we have developed a 43nM inhibitor of KDM4C.
5:50 Close of Conference