Thursday, May 22, 2014
11:15 am KEYNOTE PRESENTATION: Structures, Chemical Probes, New Biology, New Targets for Drug Discovery: Is This the Right Sequence?
Chas Bountra, Ph.D., Professor, Translational Medicine; Head, Structural Genomics Consortium, University of Oxford
In my presentation, I will discuss our partnership with nine large pharmaceutical companies to generate structure enabled, freely available, chemical probes; our collaborations with a network of academic labs to use these probes to dissect biological and disease networks; our plans to further improve target validation by using patient derived primary cells, and a new initiative to advance new clinical candidates into Phase IIa studies, pre-competitively.
12:00 pm Enjoy Lunch on Your Own
Phenotypic Screening, Target Identification and Mechanism of Action of Novel Bioactive Small Molecules
12:55 Chairperson’s Opening Remarks
Jascha Blobel, Ph.D., Product Manager, Intelligent Pharma
1:00 Systematic Assembly of Chemical Probe Libraries to Explore and Validate Novel Biology
Iván Cornella-Taracido, Ph.D., Head, Chemical Biology; Associate Director, Discovery Sciences Chemistry Innovation Centre, AstraZeneca
Chemical probes, drug-like or not, have been used for years to identify new therapeutic targets as well as to perform validation studies directed to assess their efficacious engagement and pharmacological modulation. Herein I will elaborate on the physicochemical and biological features of a good tool compound, review historical work to assemble a comprehensive, properly annotated, collection of optimal chemical probes and discuss its use towards exploratory phenotype-driven biology (target discovery) and target validation.
1:30 Systematic Chemical Biology: Building the Novartis MOA Box
Jeremy L. Jenkins, Ph.D., Senior Investigator I, Developmental & Molecular Pathways, High-Throughput Biology, Novartis Institutes for BioMedical Research
Integrating chemical bioactivity knowledge from large-scale assay data is only the first step to carrying out chemical biology robustly. To use our integrated chemogenomics data effectively, we created an automated rule-based system to score tool compounds for targets based on common-sense assertions such as potency, selectivity, and fame. Consequently, the Mechanism-of-Action Box was created, a set of important tool compounds used widely for opportunistic discovery of targets that modulate phenotypic assays. Further, the chemogenomics data is used to create thousands of probabilistic models capable of predicting targets for new compounds.
2:00 Pythia, The Way to Polypharmacology
Ignasi Belda, Ph.D., CEO, Intelligent Pharma
Pharmacological applications of a molecule stand in close relationship with the molecule's principal target. To understand this relationship, Intelligent Pharma has developed a computational technology called Pythia, which uses ligand based approaches and experimental data to predict real and off-targets for a molecule.
2:15 Chemogenomic Profiling: A Systems-Level View of the Cellular Response to Small Molecules
Guri Nina Giaever, Ph.D., Associate Professor, Faculty of Pharmaceutical Sciences, The University of British Columbia
Genome-wide characterization of the cellular response to small molecules is fundamental to understanding the cell as a system and the mechanisms of drug action in a cellular context. We profiled 3,250 diverse small molecules genome-wide in a systematic and unbiased manner, identifying 317 compounds that specifically perturb 121 unique genes. Global analysis of the dataset revealed that the majority of the cellular response to small molecules can be described by a network of chemical moiety-associated biological signatures that provide a unique resource for the discovery of functional interactions between genes, chemicals and biological processes.
2:45 An Integrated Solution to Identify Your Small Molecule Targets and Accelerate Your Drug Discovery and Development Program
Marie-Edith Gourdel, Ph.D., Director, Chemistry, HYBRiGENiCS SERVICES
Identifying protein partners of a small bioactive molecule is of great interest in the drug discovery and development process. It is a support to (i) decipher the mechanism of action after i.e. phenotypic screening, (ii) study “off-target” effects, (iii) adjust therapeutic indications and (iv) consider drug repositioning. ULTImate YChemH™ is a chemical biology tool for direct target identification. This method is based on the well-established yeast two-hybrid technology for protein-protein interactions. It benefits from ULTImate Y2H™ platform whose relevance relies on highly complex protein fragment libraries using an optimized mating procedure and its sophisticated bioinformatics tools.
3:15 Refreshment Break in the Exhibit Hall with Poster Viewing
Case Studies in Epigenetics, Protein-Protein Interactions and Novel biology
3:45 CREB Binding Protein Inhibition and Target Engagement
Lyn Jones, Ph.D., Head, Rare Diseases Chemistry; Head, Chemical Biology, Pfizer
This presentation will discuss the structure-based drug design and novel computational techniques applied to the creation of selective inhibitors of the CREBBP bromodomain. Synthetic library enablement and fragment replacement unearthed new bromodomain inhibitors, and a new technology was developed to assess bromodomain target engagement. These methods will facilitate target validation and drug discovery efforts in the epigenetic arena.
4:15 Targeting Protein-Protein Interactions as an Anticancer Strategy
Andrei A. Ivanov, Ph.D., Instructor, Pharmacology, Emory Chemical Biology Discovery Center, Emory University School of Medicine
Protein-protein interaction (PPI) interfaces represent a highly promising, although challenging, class of potential targets for therapeutic development. PPIs play a critical role in regulation of oncogenic signaling networks and they represent an expanding, but largely untapped, new space for small molecule modulator discovery. This presentation will describe our approach to discover and validate novel PPIs as potential targets for cancer therapeutics using high-throughput screening platforms.
4:45 Chemical Probing Protein Interactions of the Urokinase Receptor in Cancer
Samy Meroueh, Ph.D., Associate Professor, Biochemistry and Molecular Biology, Indiana University School of Medicine
The urokinase receptor (uPAR) is a GPI-anchored cell surface receptor at the center of an intricate network of protein-protein interactions. uPAR promotes ECM degradation and cell migration through its two immediate binding partners, the serine protease urokinase (uPA) and the extracellular matrix (ECM) component vitronectin (VTN). We present our efforts at the design of small-molecule probes to disentangle protein interactions of uPAR, and the subsequent biochemical, cellular, and computational studies to further define the contribution of these interactions in tumor invasion and metastasis.
5:15 KEYNOTE PRESENTATION: Selecting and Modulating Therapeutic Targets Using Human Biology and Chemical Biology
Stuart L. Schreiber, Ph.D., Director, Center for the Science of Therapeutics & Founding Member, Broad Institute of Harvard and MIT; Howard Hughes Medical Institute Investigator; Morris Loeb Professor, Chemistry and Chemical Biology, Harvard University
Human genetics can reveal ‘experiments of Nature’, even providing information related to a ‘dose/response’ through the analysis of allelic series of genetic variants that suggest the impact of caring about the activity of a target in terms of both efficacy and toxicity. Chemical biology can provide small-molecule modulators of the implicated targets, providing an independent means of target validation. This lecture will provide illustrations of an integrated approach to target validation using human genetics and chemical biology.
6:00 Close of Day and Workshop Registration
6:30 - 9:00 pm Dinner Workshop: Emerging Methods for Measuring Target Engagement*
The increase in usage of small molecule probes for the validation of novel therapeutic targets requires effective means of assaying target engagement in cells and living systems. Importantly, measuring the extent to which a target is engaged (or not) provides critical information regarding probe selectivity and attributed efficacy modulating a biological process, while informing of any off-target interactions and potential toxicity. The workshop is designed to discuss emerging techniques and technologies for measuring target engagement.
Instructors and Overview:
In-Cell Target Engagement and Selectivity Assessment Using Chemical Biology
Erik Hett, Ph.D., Senior Scientist, Chemical Biology, Medicinal Chemistry, Pfizer
Selectivity is a critical parameter to understand in drug discovery, yet difficult to quantify in a relevant setting, such as in cells. We have developed a novel probe to enable quantification of target engagement in disease relevant cells as well as a selectivity profiling approach. This work reveals interesting findings in terms of target engagement under different cellular environments and provides an example for how this approach can be used for other drug discovery programs.
Confirming Target Engagement in Living Systems: Examples from the Aspartyl Protease and Serine Hydrolase Enzyme Families
Andrea M. Zuhl, Ph.D., Fellow, Neuroscience, Pfizer; Former Research Associate, Cravatt Lab, The Scripps Research Institute
Chemical probes can be designed to confirm target engagement within a complex biological setting by either a compound centric or enzyme class centric approach. In an example of a compound centric design, a β-secretase inhibitor was modified into a chemical probe that allowed for successful identification and quantification of off-target activity in live cells. In a complementary approach, secondary screening of high-throughput screening (HTS) hits using a general serine hydrolase probe was used to profile a novel chemotype for serine hydrolase inhibition. Techniques to be discussed include activity and affinity-based probes, in situ and in vivo target engagement, activity-based HTS and quantitative mass spectrometry.
Physiological Relevant Target Engagement
Michael Dabrowski, Ph.D., CEO & Co-Founder, Pelago Bioscience AB
With the discovery that it is possible to quantify the thermal stability of individual proteins in complex analytes such as lysate, intact cells, tissue and body fluids, it is now possible to quantify target engagement in physiologically relevant settings. The innovative Cellular Thermal Shift Assay (CETSA™) is based on the well-known biophysical phenomenon that the melting point of a protein shifts upon binding of small molecules. CETSA™ allows for direct measurements of molecule and target protein interactions in intact cell systems and tissues from animals and humans. We have validated drug binding in mammalian cancer cell lines for a set of important clinical targets and show that a range of critical factors that are important for drug development can be identified at the target engagement level, including drug transport and activation, off-target effects, drug resistance as well as drug distribution in animal tissues. Preliminary data on drug target engagement in tumor tissue samples from patients will also be presented.
High Throughput Adaptation of the Cellular Thermal Shift Assay (CETSA) Using AlphaScreen® Technology to Monitor Target Engagement in Cells
Thomas Lundbäck, Ph.D., Assay Development & Screening, Chemical Biology Consortium Sweden; Senior Scientist, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institute
The effective binding of a ligand to a protein can be monitored by following the induced shift in thermal stability of the protein. This shift in stability is a well-known phenomenon and assays measuring such thermal shifts have been used extensively on purified proteins to detect interactions and estimate relative affinities of ligands to proteins. Here we present the implementation of a high throughput screening protocol to a thermal shift assay in a cellular format, referred to as the cellular thermal shift assay (CETSA). The method allows studies of target engagement of drug candidates in a cellular context. We have studied human p38α kinase as an example model system to demonstrate two separate protocols for CETSA. To illustrate the feasibility of applying the homogeneous assay for screening purposes we have also tested how the homogeneous assay protocol responds to the presence of a small set of test compounds taken from a diversity library.
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