Pre-con Workshop | Day 1 | Day 2 | Download Brochure
TUESDAY, APRIL 29TH
8:00 am Breakout Roundtable Discussions: Meet-the-Experts
Brainstorming discussion groups moderated by experts in the area. Attendees are invited to choose the topic ac-cording to their main interest; however, they may switch between roundtables. We emphasize that this discussion is for an interactive informal exchange among scientists and is not meant to be, in any way, a corporate or product discussion.
Table1: Fragment Library Construction
Moderator: Lance Stewart, Ph.D., President, Biostructures, deCODE Chemistry & Biostructures
• Library Size (what's optimal)
• Library Diversity (what should and should not be in the library)
• Library Handling (how to efficiently store and organize library components)
Table2: Fragment-Based Lead Discovery/Optimization: A Case of Convergent Evolution?
Moderator: Stephen K. Burley, M.D., D.Phil., Chief Scientific Officer, SGX Pharmaceuticals, Inc.
• Fragment library design considerations
• Approaches to detection of fragment hits
• Strategies for elaboration/optimization of fragment hits
Table3: SPR in Fragment-Based Drug Discovery – Benefits and Challenges
Moderator: Per Källblad, M.Sc. Ph.D., CEO, Beactica AB
• SPR-optimized fragment libraries
• Prioritizing the hits
• Kinetics and selectivity on the fragment level
Table 4: Title to Be Announced
Moderator: Andrew J. Woodhead, Ph.D., Senior Chemist, Chemistry, Astex Therapeutics Ltd.
Table 5: Fragment Libary Considerations
Moderator: Lena Tagmose , Ph.D., Section Head, Computational Chemistry , H Lundbeck AS
• Does a fragment need to be directly open to chemical derivitisation or is a strategy based upon the availability of incrementably
larger molecules that contain the fragment suuficient (or better) ?
• Should a fragment library for targets where the indication is CNS be designed differently?
• How important is Ligand Efficiency in evaluating fragment hits, and is Lipophilic Ligand Efficiency even more important, to ensure specific interactions?
Table 6: Fragment Libary Considerations
Lena Tagmose , Ph.D., Section Head, Computational Chemistry , H Lundbeck AS
• Does a fragment need to be directly open to chemical derivitisation or is a strategy based upon the availabilty of incrementably
larger molecules that contain the fragment suuficient (or better) ?
• Should a fragment library for targets where the indication is CNS be designed differently?
• How important is Ligand Efficiency in evaluating fragment hits, and is Lipophilic Ligand Efficiency even more important, to ensure specific interactions?
APPLIED FBDD
9:00 Chairperson’s Remarks
Stephen K. Burley, M.D., D.Phil., Chief Scientific Officer and Senior Vice President Research, SGX Pharmaceuticals, Inc.
9:05 Discovery and Development of Selective, Orally Bioavailable Tyrosine Kinase Inhibitors for Targeted Treatment of Human Cancers
Stephen K. Burley, M.D., D.Phil.
The SGX platform utilizes high-throughput X-ray crystallography to guide fragment-based lead identification and subsequent optimization of potency, selectivity, and other drug-like properties. Biologically active compound series are prioritized for further medicinal chemistry and preclinical development efforts using the results of in vitro and in vivo ADME and in vitro toxicology studies. Recent progress with inhibitors of the MET receptor tyrosine kinase (SGX523—Clinical; SGX126—Preclinical) and of drug-resistant BCR-ABL (SGX393—Preclinical) will be discussed. MET represents a potentially important target across a wide range of cancer indications, wherein a per-sonalized-medicines approach may prove particularly beneficial. BCR-ABL is the target for treatment of chronic myeloid leukemia, for which approved 1st and 2nd generation inhibitors are encountering resistance in patients.
9:35 Fragments of LifeTM (FOL) for Lead Identification and Optimization
Lance Stewart, Ph.D., President, Biostructures, deCODE Chemistry & Biostructures
Small molecules of life carry natural born information content, and through co-evolution with proteins they are likely to have high ligand efficiency for protein binding. Inspired by this concept, we have developed a novel Fragments of Life™ library for lead identification and optimization in conjunction with protein X-ray crystallogra-phy. The Fragments of Life™ library includes molecules of life, secondary metabolites, mimetics of protein archi-tecture, and hetero-functional derivatives thereof, each selected for pharmaceutic properties, water solubility, and potential for chemical elaboration to facilitate medicinal chemistry efforts. The application of Fragments of Life™ technology to both metabolic and infectious disease targets has yielded hit rates of 2-8%, allowing the rapid identification of multiple lead series templates. The fragment binding information has expanded our understanding of the structure activity relationships for known inhibitors of a metabolic target and has facilitated chemotype switching experiments in two synthetic cycles, converting a ~350 uM potent fragment to a ~10 nM potent back-up compound to a clinical candidate, as measured in human whole blood cell assays. The Fragments of Life™ technology affords the possibility of uncovering connections between metabolic pathways by understanding the preference of proteins for binding to fragments with chemical architectures shared by known molecules of life.
10:05 Technology Watch (Sponsorship Available)
10:20 Networking Coffee Break, Poster & Exhibit Viewing
11:00 Discovery of Novel Protein Kinase Inhibitors Using Fragment-Based Screening
David Williams, Ph.D., Vice President, Biology & Structural Sciences, Sareum Ltd.
11:30 REPLACE – A Strategy for Fragment-Based Design of Protein Kinase Inhibitors
Campbell McInnes, Ph.D., Assistant Professor, Pharmaceutical Sciences, University of South Carolina
A fragment - based design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) is described in which nonpeptidic surrogate fragments for specific determinants of known peptide ligands are identified in silico using a core peptide-bound protein structure as a design anchor. In the REPLACE application example the effective replacement of two critical binding motifs in a protein kinase inhi-bitor pentapeptide with more drug-like phenyltriazole and diphenyl ether groups is presented. These were identified using high-throughput docking of fragment libraries onto the target-bound termini of suitably truncated forms of the inhibitor peptide. Proof of concept for this strategy was thus obtained through the identification of potent peptide-small molecule hybrids and by the confirmation of inhibitor binding modes in X-ray crystal structures. This method obviates the requirement for a high sensitivity-binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors of protein-protein interactions to generate pharmaceutically acceptable lead molecules.
12:00 Close of Fragment-Based Drug Discovery