Archived Content

Cambridge Healthtech Institute's Seventh Annual
Fragment-Based Drug Discovery
April 17-18 

Day 1 | Day 2
Download Drug Discovery Chemistry Brochure or Fragment-Based 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

Roderick E. Hubbard, Ph.D., Vernalis Ltd.


» 8:10 KEYNOTE PRESENTATION 

NMR Guided Approaches to FBDD: From Fragment Identification to uHTS by NMR 

Maurizio Pellecchia, Ph.D., Professor, Chemical Biology, Sanford-Burnham Medical Research Institute and AnCoreX Therapeutics 

 Recently, fragment based ligand design (FBLD) approaches have become more widely used in drug discovery projects from both academia and industry, and are even often preferred to traditional ultra-high-throughput screening (uHTS) of large collection of compounds (>105). A key advantage of FBLD approaches is that these often rely on robust biophysical methods such as NMR spectroscopy for detection of ligand binding, hence are less prone to artifacts that too often plague the results from uHTS campaigns. However, the challenge of FBLD approaches is that the evolution of initial weakly interacting fragments into more mature compounds with low micromolar is not trivial. In this lecture I will reiterate the most commonly used NMR approaches to guide these steps and will introduce a new fragment screening strategy, that takes advantage of both, the robustness of protein NMR spectroscopy as the detection method, and the basic principles of combinatorial chemistry to enable the screening of large libraries of fragments pre-assembled on a common backbone (>105 compounds). Hence we term the approach uHTS by NMR.  


SCREENING OF FRAGMENTS 

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 

NMR 

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 were 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
Selcia logo small
11:15 The CEfragTM Screen: Fragment Screening using Capillary Electrophoresis

Carol Austin, Ph.D., Biology Group Leader, SelciaFragment based screening is a popular, successful approach for hit identification in drug discovery.  Selcia have successfully developed a capillary electrophoresis-based method to detect weak fragment binding interactions with soluble protein targets. The technique is applicable to a broad range of targets, in particular those that are not amenable to tethering.  Using the Selcia fragment library, weak affinity inhibitors have been successfully identified against a variety of target classes and these have been validated using other techniques.

 

CURRENT STRATEGIES AND FUTURE FIELDS 

11:30 Fishing from Known Fragments into New Chemical Space

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.


DiscovRx
12:00 pm Luncheon Presentation I
KINOMEscan™:  A Comprehensive Biochemical Screening Solution for Kinases and Emerging Epigenetic Drug Targets
Paul Gallant, DiscoveRx 



GE Healthcare logo small
12:30 Luncheon Presentation II 
To Affinity and Beyond: SPR Analysis in Fragment Based Lead Generation
Cynthia Shuman, Ph.D., Application Scientist - Biacore, Research Sciences, GE HealthcareSPR is becoming a powerful tool in lead generation due to the sensitivity required to identify and rank low-affinity and low-molecular weight compounds binding to their targets, information which is critical during hit-to-lead development. 


1:25 Chairperson’s RemarksEdward Zartler, Ph.D., President & CSO, Quantum Tessera Consulting, LLC and ZoBio 

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 Selected Oral Poster Presentation:
Polo-Like Kinase 1: A Fragment-Based Approach

Christopher Stubbs, Department of Chemistry, University of Cambridge

3:15 Networking Refreshment Break in Exhibit Hall with Poster Viewing

  

BACE INHIBITORS 

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



Day 1 | Day 2
Download Drug Discovery Chemistry Brochure or Fragment-Based Brochure