Cambridge Healthtech Institute 第1届
第15届Discovery on Target其中一环
RECOMMENDED ALL ACCESS PACKAGE:
· September 25 Symposium: Constrained Peptides and Macrocyclics
· September 25 Short Course: Covalent Fragments: Applications in Target-Based and Phenotypic Screens
· September 26-27 Conference: Lead Generation Strategies
· September 27-28 Conference: Autoimmune and Inflammation Drug Targets
· September 27 Short Course: Introduction to Targeted Covalent Inhibitors
· September 28-29 Symposium: Tackling Rare Diseases
Day 1 | Day 2
Tuesday, September 26
7:00 am Registration Open and Morning Coffee
Strategies for Finding and Funneling Drug Leads
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
Strategies for Finding and Funneling Drug Leads (Cont.)
10:25 Following 1-Carbon Metabolism to Find New Cancer Drug Leads
Nello Mainolfi, Ph.D., Senior Director, Head of Drug Discovery, Raze Therapeutics
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
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/IKK· 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 Using Biophysics to Probe the Biological Relevance of Fragment-Binding Sites
Susanne Saalau, Ph.D., Director, Molecular Science, Astex Pharmaceuticals
Astex's X-ray Fragment Screen often discovers novel binding sites on targets of interest for which no literature precedent is available. Through the implementation of orthogonal biophysical methods such as SPR, ITC, and MS, we probe the sites to determine which are druggable and mechanistically or allosterically relevant. I will present case studies to show how Astex has prosecuted a variety of difficult targets including PPI's to validate alternative sites.
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
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
Fragment-Assisted Approaches (Cont.)
4:05 Biophysical Fragment Screening Success When HTS Leads Nowhere
Peter Coombs, Ph.D., Senior Scientist, Assay Development & Screening Group, MRC Technology
Fragment screening at MRCT 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. Key case studies will be presented.
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 available on the conference website.
6:05 Welcome Reception in the Exhibit Hall (Sponsorship Opportunity Available)
7:10 Close of Day
Day 1 | Day 2
Wednesday, September 27
7:30 am Registration Open and Morning Coffee
Beyond Biophysical Approaches for Lead Generation
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.
9:05 Sponsored Presentation (Opportunity Available)
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
Biophysical Approaches for Membrane Proteins
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
12:20 pm Plenary Keynote Program
(click here for details)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing
2:45 Close of Conference