2017 Archived Content
A paradigm shift is underway in the biopharma industry due to advances in biophysical techniques and their applications to drug discovery. Typically, early phase drug discovery comprised of hit generation followed by lead optimization. However now the two processes are often combined into one, referred to as lead generation. Traditional hit-finding techniques use high throughput screening coupled to biochemical assays to screen small molecule libraries with a large number of chemical entities. However now with the improvement in speed and automation of biophysical techniques such as NMR and sensor-based assays that detect the interactions between molecules, more information-revealing biophysical assays can be used to screen smaller but more focused libraries. This work has involved discovery biologists and chemists working together from the start. Cambridge Healthtech Institute’s Inaugural Lead Generation Strategies conference will bring together these scientists to delve into which targets are being addressed and how by these new approaches — are some targets more amenable to particular techniques? Updates on biophysical approaches in the context of specific drug discovery projects will also be covered.
Final Agenda
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Tuesday, September 26
7:00 am Registration Open and Morning Coffee
8:00 Welcome Remarks
Anjani Shah, Ph.D., Conference Director, Cambridge Healthtech Institute
8:05 Chairperson’s Opening Remarks
Kevin Lumb, Ph.D., Director, Discovery Sciences, Janssen R&D
8:10 FEATURED PRESENTATION: Quantity vs. Quality in Lead Discovery
Jeff Hermes, Ph.D., Director, Chemical Biology, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
Nearly two decades ago, a push for screening of millions of compounds drove HTS labs to reduce assay volumes, increase plate densities and simplify assays. Are there still compelling reasons to use enormous, chemically diverse libraries in a “one and done” approach, or are there smarter, more informed ways to screen? This lecture will make the case for integrated and iterative screening with higher quality assays and libraries.
8:40 FEATURED PRESENTATION: FBDD: Part of an Integrated Drug Discovery Platform
Derek Cole, Ph.D., Director, Medicinal Chemistry, Takeda
This presentation will focus on the establishment of an efficient fragment-based drug discovery (FBDD) platform to enable fragment hit identification and FBDD/SBDD-based lead optimization to provide lead series and/or tool compounds to test pharmacological hypothesis. We will also share ongoing efforts to extend FBDD philosophies, strategies and technologies to more challenging targets, including GPCRs and other membrane proteins.
9:10 Knowledge Versus Deception: The Art of Triage
Michael A. Walters, Ph.D., Director, Lead and Probe Discovery, ITDD (Institute for Therapeutics Discovery and Development); Research Associate Professor, Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota
HTS is often the genesis of lead compounds. Given the constrained resources available for hit-to-lead projects, it is imperative that the prioritization of compounds for follow-up (triage) is knowledge-based and holistic. The art of triage incorporates chemistry knowledge, concerns itself with physicochemical properties and not only activity, and recognizes the often-deceptive nature of certain compound classes. Practical guidelines for effective HTS triage will be presented.
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:25 A Novel Series of 3-Posphoglycerate Dehydrogenase Inhibitors and its Cellular Phenotypes
Nello Mainolfi, Ph.D., Senior Director, Head of Drug Discovery, Raze Therapeutics
PHGDH (3-phosphoglycerate dehydrogenase) is the first enzyme branching from glycolysis into the serine synthetic pathway. Increases in PHGDH expression (mRNA and protein levels) have been observed in nearly 70% of estrogen receptor-negative breast cancers. We have been able to successfully identify first in class small molecule inhibitors with nanomolar cellular potency, high degree of selectivity and oral bioavailability
10:55 Delineation of Screening Hits by NMR Spectroscopy: The Good, the Bad and the Ugly
Mary Harner, Ph.D., Research Investigator II, Mechanistic Biochemistry, Bristol-Myers Squibb R&D
While early-phase hits originate from disparate screening approaches, assay formats and libraries, they share one commonality: the need for direct (i.e. biophysical) on-target binding confirmation. As a biophysical tool, NMR spectroscopy is uniquely situated to provide quality control, direct binding, and mechanistic binding assessments on small molecule hits, in addition to its well-documented application as a fragment screening approach. Case studies will be presented that champion NMR’s ability to detect direct binding of hits when all else fails.
11:25 CryoEM for Drug Discovery Applications
Sriram Subramaniam, Ph.D., Senior Investigator, Head, Biophysics Section, Laboratory of Cell Biology, National Institutes of Health
Recent breakthroughs in the field of cryo-electron microcopy (cryo-EM) provide new prospects for determination of the structures of a variety of medically important macromolecular assemblies. In my talk, I will discuss the broader context of the development of cryo-EM methods for studying protein complexes and viruses, and provide an overview of the potential of these advances for the development of improved therapeutic agents.
11:55 Building on Fragment-Based Drug Design
Trevor Perrior, Ph.D., CSO, Domainex
The Domainex FragmentBuilder platform is based on our proprietary library, high-throughput microscale thermophoresis for fragment screening, and structure-based optimisation capability. This technology will be illustrated with case studies on the lysine methyltransferase, G9a; and on the work that led to the Domainex TBK1/IKKƐ inhibitor drug candidate, DMXD-011.
12:25 pm Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson’s Remarks
Derek Cole, Ph.D., Director, Medicinal Chemistry, Takeda California
1:55 Experiences of X-ray crystallographic screening at Astex
Andrew Woodhead, Ph.D., Director, Chemistry, Astex Pharmaceuticals
X-ray crystallography has been the cornerstone of fragment screening at Astex for the past 15 years. Over that time, information gleaned from thousands of proprietary protein-ligand crystal structures across a wide range of protein families has been highly influential. This presentation will describe how this structural information has led to the evolution of Astex’s fragment library, helped to identify novel binding sites and unravel new mechanisms of action, plus most importantly, has provided a platform to develop drugs to provide benefit to patients.
2:25 Integrating Novel Biophysical Approaches in Fragment-Based Lead Discovery Workflow: MST and nDSF for Screening and Validation
Alexey Rak, Ph.D., Head of Bio Structure and Biophysics, Integrated Drug Discovery, Sanofi R&D
The search for optimal combinations of biophysical techniques for fragment-based lead discovery that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. Here we present an approach utilizing automated microscale thermophoresis (MST) affinity screening to identify fragments active against human kinase. MST in concert with nDSF identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods.
2:55 Generating Small Molecule Probes in Target-Agnostic Style
Haiching Ma, CSO, Reaction Biology Corporation
Both epigenetics and human kinome biology are currently major focuses of basic research and drug discovery efforts. However, members of each of these target classes belong to larger protein families, other members of which may have biological functions distinct from those of epigenetic modifiers or kinases while nevertheless having similar protein structures. Reaction Biology Corporation (RBC) brings its extensive working experience in epigenetics and human kinome biology to meeting such challenges to target specificity and selectivity and has served thousands of companies and universities worldwide in their drug discovery efforts. We will present our budget-friendly, rapid turnaround, high-throughput chemical biology strategies and show how we could help your Project Teams to generate chemical probes and lead materials by delivering high quality data and support.
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05 Biophysical Fragment Screening Success When HTS Leads Nowhere
Peter Coombs, Ph.D., Senior Scientist, Assay Development & Screening Group, LifeArc (new name for MRC Technology)
Fragment screening at LifeArc (the new name for MRC Technology) has developed into a core lead generation resource. Combining orthogonal biophysical approaches, particularly focusing on SPR and thermal shift assays, with in silico fragment docking, site-directed mutagenesis and early medicinal chemistry, has allowed us to successfully prosecute challenging enzyme and PPI targets which have failed to produce leads in HTS. I will present key case studies describing how we have used biophysical approaches on targets for Alzheimer's, immuno-oncology and metastatic breast cancer, including an example where lead fragments have since been progressed into selective nanomolar inhibitors of a novel cancer target in the absence of X-ray crystal structures.
4:35 Bromodomain Candidates Discovered by an Integrated Lead-Generation Platform
Pawel Sledz, Ph.D., Senior Research Associate, Department of Biochemistry, Caflisch Laboratory, University of Zurich
We developed an efficient in silico lead generation platform based on a high-throughput fragment-docking engine. The docked poses are used as a starting point to propose single-step chemical modifications of the fragment-hits to generate a library of lead candidates. I discuss its application to the development of high-affinity blockers of non-BET bromodomains, potential candidates for cancer and Alzheimer’s disease therapy.
5:05 Interactive Breakout Discussion Groups
Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below. Please click here for full details on all breakouts.
DNA-Encoded Libraries
Moderator: Christopher Arico-Muendel, Ph.D., Manager, Platform Capabilities, Encoded Library Technologies, R&D Platform Technology & Science, GlaxoSmithKline
- Different types/approaches (i.e., DNA recorded, DNA templated libraries)
- Current constraints on DNA-Encoded Libraries (DNA compatible chemistry, Library Diversity, Selection Methods)
- Applications/target classes
Fragment-Based Drug Design Challenges
Moderator: Susanne Saalau, Ph.D., Director, Molecular Science, Astex Pharmaceuticals
- FBDD in absence of x-al structure
- Pros and cons of X-ray crystallography as primary screen
- Orthogonal FBDD screening approaches: TSA, NMR, SPR, high content, phenotypic
- Library design challenges
Integrating Phenotypic Screening into Lead Generation
Moderator: Paula M. Loria, Ph.D., Associate Research Fellow, Primary Pharmacology Group, Discovery Sciences, Pfizer
- How used for HIT ID and validation – examples from the group
- How used to support SAR
- Setting up a screen from scratch
6:05 Welcome Reception in the Exhibit Hall (Sponsorship Opportunity Available)
7:10 Close of Day
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Wednesday, September 27
7:30 am Registration Open and Morning Coffee
8:00 Chairperson’s Remarks
Mary Harner, Ph.D., Research Investigator II, Mechanistic Biochemistry, Bristol-Myers Squibb R&D
8:05 Never Say Never: Phenotypic Screening Uncovers a Novel Mechanism for Regulation of PCSK9
Paula M. Loria, Ph.D., Associate Research Fellow, Primary Pharmacology Group, Discovery Sciences, Pfizer
The power and challenge of phenotypic screening is that it can be unbiased to the mode of action of test compounds and thus has the capacity to sample new biology. We have identified small molecules that selectively stall PCSK9 translation via direct interaction with the ribosome. I will discuss the screening and hit deconvolution approaches we applied in the discovery of these intriguing drug candidates.
8:35 Discovery of BET Inhibitor Lead Molecules Using DNA-Encoded Library Technologies
Gang Yao, Ph.D., Senior Scientist, Encoded Library Technology Group Drug Design & Selection Boston, GSK
The bromo and extra C-terminal domain (BET) family of bromodomain-containing proteins are important regulators of the epigenome and their dysfunction have been linked to disease. This talk describes the discovery of novel BET inhibitors using the encoded library technology (ELT). Further optimization of the hits led to a high-quality drug-like inhibitor that displayed a high level of target engagement and favourable oral PK properties.
9:05Network-Driven Drug Discovery (NDD) - A Unique Lead Generation Platform
Colin Stubberfield, Head, Drug Discovery, e Therapeutics plc
The majority of drug discovery approaches involve the search for a single binding target in a well-characterised pathway. But while pathways are easy to envisage, they do not reflect the complexity of biological systems. A more realistic way to describe the underlying interactions which occur is as a network. However, to exploit this view of biology in drug discovery a new process must be considered. I will describe our approach and its successful implementation.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 NMR Spectroscopy and Integrative Structural Biology of Human GPCRs
Matthew Eddy, Ph.D., Postdoctoral Fellow, Laboratory of Raymond Stevens, The Bridge Institute, University of Southern California
Nuclear magnetic resonance (NMR) spectroscopy complements other structural biology techniques, such as x-ray diffraction, by identifying multiple simultaneously populated conformations in equilibrium. Here, we leverage this advantage to study two human GPCRs. First, we report how a GPCR fusion strategy used for x-ray crystallography influences the protein conformational equilibrium and highlight potential cases where drug-ligand interactions can be affected. Second, we report a novel approach to incorporation of stable isotopic NMR labels into a wild type human GPCR and new insights obtained from this method.
10:50 Next Generation Bio-Sensing: New Opportunities for Challenging Targets
Tim Kaminski, Ph.D., Postdoctoral Fellow, Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg
Single molecule experiments enable us, next to its unmatched sensitivity, to directly gain a mechanistic insight into biological processes by observing its stochastic behavior. We are developing a toolbox which advances single molecule microscopy from a method primarily used in academia into a versatile tool for drug discovery. By using this method, we are able to address shortcomings of established biophysical methods as e.g. tight binding limit, working with membrane proteins, higher throughput. Additionally, we are able to extract kinetic profiling of inhibition reactions in solution by observing the association and dissociation of thousands of molecules in parallel with a surface-based single molecule platform.
11:20 Enjoy Lunch on Your Own
12:35 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Close of Conference
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