Fragment-Based Drug Discovery
From Discovery to Lessons Learned
April 24-25, 2014
Fragment-based approaches for finding potential new medical therapies are now a part of many drug discovery programs. There are at least 25 disclosed drug candidates forging ahead in clinical development whose origins can be traced to fragment-based screening campaigns. However medicinal chemists, especially in larger companies with high throughput screening departments, have other sources for ‘hits’ to optimize into lead drug candidates. What is the exact role and usefulness of fragment-based screening nowadays? How is it changing? How can it be improved? How can it be better integrated or used synergistically with other approaches? Join your discovery chemistry peers at Cambridge Healthtech Institute’s ninth annual Fragment-Based Drug Discovery meeting to discuss these questions and hear presentations about the ever present challenge for medicinal chemists: optimization strategies to get to better drugs from fragment hits.
A mutli-disciplinary gathering where you can gain new insights and refresh on new ideas
Djamal B., Arisan Therapeutics
through networking and presentations
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12:30 pm Registration
1:30 Chairperson’s Opening Remarks
Daniel A. Erlanson, Ph.D., President & Co-Founder, Carmot Therapeutics, Inc.
1:40 Using Fragments with Confidence
Ben Davis, Ph.D. Research Fellow, Biology, Vernalis
In fragment-based ligand design, it is vital to have a high level of confidence in the initial fragment hits in order to exclude potentially misleading artifacts. I will discuss ways of avoiding some of the common pitfalls which can bedevil an FBLD campaign, in order to define a well validated set of hits. I will also discuss examples where FBLD has been integrated with other approaches to generate novel, optimized lead compounds.
2:10 Fragment-Based Approaches for Drugging Proteases
Steven J. Taylor, Ph.D., Director, Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc.
Fragments are components of drug-like molecules that are low molecular weight and can be pre-filtered for favorable physicochemical properties. The Boehringer Ingelheim fragment deck contains approximately 3000 fragments that have been screened against a number of difficult to drug targets including proteases. In this talk we describe our Fragment to Lead efforts that resulted in potent, selective MMP-13 and Chymase inhibitors. Lessons learned from these efforts are transferrable to other lead identification campaigns.
2:40 Evolution of Fragments in the Absence of Crystal Structures
Peter Kutchukian, Ph.D., Associate Principal Scientist, ChemInformatics, Merck and Co.
While FBS offers an efficient avenue to sample chemical space, FBS campaigns are primarily executed for targets that can be readily crystallized, ultimately limiting its scope. A new strategy that extracts information from fragment campaigns, and leverages the information to identify small molecules with enhanced potency and diverse chemotypes without using any target structural information will be described, as well as its application to specific case studies.
3:10 Targeting Specific Interactions to Improve Binding Properties of EGFR-Kinase Ligands
Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group
A structure-based drug design modeling program, combined with PDB data-mining, protein structural fingerprints and pharmacophore searches was used to help identify and characterize linkers for connecting EGFR-binding moieties to DNA and Src targeting functionalities. The resulting compounds showed EGFR inhibitory potency in the low micromolar to nM range and retained significant activity against their divergent targets.
3:40 Refreshment Break in the Exhibit Hall with Poster Viewing
4:20 Fishing for Fragments to Complement Known Binders
Daniel A. Erlanson, Ph.D., President and Co-Founder, Carmot Therapeutics, Inc.
Finding fragments is now routine, but advancing them to leads can be difficult. Linking two fragments is complicated by getting the linker just right. In contrast, using a known binder as an anchor from which to “fish” for fragments identifies only those connected by suitable linkers. Chemotype Evolution applies this strategy to provide a general solution to the problem of how to turn promising fragments into promising leads.
4:50 Fragment vs. HTS Hits: Does it Have to be a Competition?
Nicholas J. Skelton, Ph.D., Senior Scientist, Department of Discovery Chemistry, Genentech, Inc.
Fragment-based approaches are often viewed as a being in competition with high-throughput biochemical screening to identify hits to initiate drug discovery programs. Combining data from both approaches can often be beneficial. I will describe recent fragment-based lead discovery efforts at Genentech that have complemented results from biochemical screening.
5:20 Breakout Discussions
In this session, attendees choose a specific roundtable discussion to join. Each group has a moderator to ensure focused conversations around key issues within the topic. The small group format allows participants to informally meet potential collaborators, share examples from their work and discuss ideas with peers. Check our website in February to see the full listing of breakout topics and moderators.
6:20 Close of Day
6:30 Dinner Short Courses*
*Separate registration required; please click here for details.
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