Cambridge Healthtech Institute's Seventh Annual
Fragment-Based Drug Discovery
April 17-18
Day 1 | Day 2 | Download Brochure
Finding fragments by various screening methods has become an established practice. Each of the technologies used have a different set of advantages and disadvantages. Questions such as how to select the most suitable projects, how and when to use screening methods such as crystallography, NMR, SPR or mass spec either as a standalone technique or in combination and how to correctly predict binding at active sites will be addressed in this meeting. In addition, new challenges are arising and will be discussed, such as fragment docking, fragment library design, ligand efficiency, fragment selecitivity and specificity.
TUESDAY, APRIL 17
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
» 8:10 KEYNOTE PRESENTATION
Maurizio Pellecchia, Ph.D., Professor, Burnham Institute for Medical Research
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8:50 Virtual Screens of Fragments against a Panel of HIV Protease Variants on FightAIDS@Home Discovered Two Novel Inhibitors
Alex L. Perryman, Ph.D., Research Associate, Professor Art Olson’s Molecular Graphics Lab, Department of Molecular Biology, The Scripps Research Institute
FightAIDS@Home is an internet-distributed computing project that is part of IBM’s “World Community Grid.” In one experiment 12,000 fragments were AutoDocked against the active site and the “eye site” of a panel of different drug-resistant mutants and w.t. strains of HIV protease. The top-ranked compounds were then re-evaluated against 9 different variants of HIV protease using the new docking program “AutoDock Vina.” Of the 10 fragments we ordered and assayed, two novel, active inhibitors were discovered.
9:20 Fragments and Challenging Targets
Roderick E. Hubbard, Ph.D., Vernalis Ltd.
Fragment techniques are now well established for drug discovery against conventional drug targets such as kinases, ATPases and proteases. Where there is real excitement is in using the methods to find hit start points against targets where the drug binding sites are less well behaved. I will discuss the approaches which can be used to address these challenges.
9:50 Networking Coffee Break
10:15 Using New Tools for an Old Target: Finding Active Ligands to a Novel Binding Site in Kras Using Solution State NMR
Till Maurer, Senior Scientist, Structural Biology, Genentech, Inc.
NMR fragment based lead discovery was applied to the oncology target kRAS. Ligands to a novel binding site was identified using ligand and protein NMR methods. X-ray crystallography successfully showed a well resolved binding mode and biochemical assays demonstrated activity. All three methods allowed to conclude the mode of action.
10:45 You Want to Put Your Fragment Where? Targeting the Next (And Really Hard!) Generation of Targets
Edward Zartler, Ph.D., President & CSO, Quantum Tessera Consulting, LLC and ZoBio
The low hanging fruit has all been picked. The next generation of targets are more complex (and more difficult) which will require re-thinking how to screen them. These targets include unfolded (or intrinsically disordered), protein-protein interactions, multi-protein complexes, and a variety of targets no one would have touched a decade ago. NMR spectroscopy is a well-known screening and H2L follow-up technique that will have major impact in delivering hits on these next generation of techniques. This talk will discuss the obstacles these targets represent and ways that NMR (and other techniques) can be used to overcome them.
Sponsored by
11:15 The CEfragTM Screen: Fragment Screening using Capillary Electrophoresis
Carol Austin, Ph.D., Biology Group Leader, Selcia
11:30 Fishing from Known Fragments into New Chemical
Daniel Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.
Finding fragments is now routine, but advancing fragments to leads remains challenging. Linking two fragments can boost potency, but this strategy is usually undermined by imperfections in the linker. In contrast, using one fragment as an anchor from which to “fish” for a second fragment identifies only fragments connected by a suitable linker. Chemotype Evolution applies this strategy and provides a general solution to the problem of how to turn promising fragments into promising leads.
12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:25 Chairperson’s Remarks
1:30 Selectivity in Fragment-Based Drug Discovery
Marcel Verdonk, Ph.D., Director, Computational Chemistry and Informatics, Astex Therapeutics, Inc.
In drug discovery, the selectivity profile of compounds is of critical importance to their biological activity and their toxicity. Here we will discuss Astex’ findings on obtaining selectivity from our experiences in fragment-based drug discovery. We find that fragment hits display a range of selectivity profiles, both against closely-related and more distant targets. Trends across this data (in terms of both fragment and target properties) will be discussed, along with the difficulties associated with assembling and analysing the dataset. Examples of fragments with inherent selectivity between related targets will also be discussed. Finally, we will show several examples of how selectivity can be achieved by carefully optimising fragment hits into leads, using structure-guided design.
2:00 Probing G Protein-Coupled Receptors (GPCRs) with Fragments, New Approaches for Old Targets
Iwan de Esch, Ph.D., Associate Professor, Medicinal Chemistry, VU University Amsterdam
In recent years, highly innovative fragment-based drug discovery technologies and approaches have been developed for a variety of drug target classes and these can now be used to study ligand-GPCR interaction. Some of these receptors have been studied for more than a decade, and allow for an evaluation of the different approaches.
2:30 REPLACE Fragment-Based Strategy
Campbell McInnes, Ph.D., Associate Professor, Medicinal Chemistry, University of South Carolina
3:00 Sponsored Presentation (Opportunity Available)
3:15 Networking Refreshment Break in Exhibit Hall with Poster Viewing
4:00 Multidisciplinary Approach to Optimization of Weak Benzimidazole BACE1 Fragment Hits
Ivan Efremov, Ph.D., Senior Principal Scientist, Neurosciences Chemistry, Worldwide Medicinal Chemistry, Pfizer, Inc.
Fragment screening campaigns often produce multiple hits with a range of affinity to the target of interest. Hits with very low affinity and no structural information tend to be regarded as significantly less promising and, naturally, are more difficult to prosecute. This presentation will describe optimization of a very weak series of beta-secretase fragment hits that was made possible by application of a multidisciplinary approach. Prediction of a binding mode using several computational techniques and institutional knowledge allowed to formulate testable hypotheses for hit optimization work. The bona fide chemical matter was discovered as the result of these efforts.
4:30 Fragment-Based Design and Clinical Translation of BACE Inhibitors
David Timm, Ph.D., Group Leader, Research Advisor, Structural Biology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis
Cerebral deposition of amyloid-ß peptide (Aß) is critical in Alzheimer’s disease (AD) pathogenesis. Aß generation is initiated when ß-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376, the first orally available non-peptidic BACE1 inhibitor that produces profound Aß -lowering effects in animals, and importantly, translates into strong and long-lasting Aß reduction in human CNS. Our studies with LY2811376 demonstrate that BACE1 is a tractable small-molecule target with promise for the development of AD therapeutics.
5:00 Identification of an in vivo Efficacious BACE1 Inhibitor Derived From Fragment Screening
Ted Judd, Ph.D., Senior Scientist, Amgen, Inc.
5:30 - 6:30 Networking Reception in the Exhibit Hall with Poster Viewing
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