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.
Topic 4: Fragment Libraries and the 3rd Dimension
Moderator: Damian W. Young, Ph.D., Assistant Professor, Departments of Pathology and Immunology and Pharmacology; Assistant Director, Center of Drug Discovery, Baylor College of Medicine
• What is 3D fragment chemical space and how much diversity is needed to capture it?
• What are the advantages and challenges related to screening 3D fragments?
• What examples demonstrate the utility of 3D fragments within a fragment screening collection?
Topic 5: Integrating Fragment-based and High Throughput Screening (HTS) Leads
Moderator: Peter Kutchukian, Ph.D., Associate Principal Scientist, ChemInformatics, Merck and Co.
• De-Fragmentation Approaches: breaking HTS leads into fragments
• Using Fragments to find better HTS leads
• Facilitating department collaborations
Topic 6: Practical Aspects of Fragment Screening
Moderator: Derek Cole, Ph.D., Director, Chemistry, Takeda California
• Building and storing your library.
• How do you screen your fragments?
• What are some pitfalls and how do you avoid them?
• Success rates with each method.
• Fragment follow up? (i.e. methods you choose, requirement of structural information (andhow do you get it))
6:20 Close of Day
6:30 Dinner Short Courses*
*Separate registration required; please click here for details.
7:30 am Morning Coffee
8:00 Chairperson’s Remarks
Peter Kutchukian, Ph.D., Associate Principal Scientist,ChemInformatics, Merck and Co.
8:05 Fragment-Based Discovery in 3D Utilizing Diversity-Oriented Synthesis
Damian W. Young, Ph.D., Assistant Professor, Departments of Pathology and Immunology and Pharmacology; Assistant Director, Center of Drug Discovery, Baylor College of Medicine
Fragment chemical space has traditionally relied heavily on the use of highly sp2 carbon atom enriched aromatic compounds. Accordingly, it is rational to consider that a limited subset of biological space can be targeted with such compounds. We have utilized diversity-oriented synthesis as a guiding algorithm to produce fragments having greater sp3/sp2 carbon atom ratios toward the goal of engaging a wider spectrum of biological targets using fragment-based drug discovery.
8:35 New Developments in NMR
Isabelle Krimm, Ph.D., Fragment-Based Screening & NMR Team, Institute of Analytical Sciences, University of Lyon, CNRS
Fragment screening resides in the identification of minimal motifs responsible for the specific protein-ligand recognition. Once fragment hits have been identified, one needs to ensure that the fragments exhibit a specific binding mode. We will see how NMR can be used, if crystallographic resolution of protein-fragment complexes fails. In addition, we will see how to assess whether the protein undergoes conformational changes upon fragment binding.
9:05 Using Fragment and HTS Approaches to Identify Modulators of the Ubiquitin-
selective Segregase p97
Stacie Bulfer, Ph.D., Postdoctoral Scholar, Laboratory of Michelle Arkin, Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco
The hexameric ATPase p97 functions in ubiquitin-dependent degradation pathways by segregating proteins from protein-complexes. Each monomer of the highly dynamic p97 enzyme is composed of three major domains: an N-terminal PPI domain and two ATPase domains (D1 and D2). Here, several approaches including SPR, NMR and HTS are used to selectively target distinct domains of p97 to modulate overall activity.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing
10:20 Fragment-Based Approaches to Study GPCR Biased Signaling
Iwan de Esch, Ph.D., Professor, Medicinal Chemistry, VU University, Amsterdam
We have performed fragment library screening on a list of GPCR targets and not only determined binding affinities but also agonist and antagonist activity on both G-protein mediated signalling and on b-arrestin mediated signalling. The data illustrates the delicate differences in biased signalling when performing FBDD on GPCR targets. The presentation will also reflect on remarkable differences in binding kinetics during fragment growing.
10:50 Nanobody-Enabled Fragment Screening on Active-State Constrained GPCRs
Jan Steyaert, Ph.D., Director, Structural Biology Brussels Research Center, Vrije University Brussels
Last year our lab showed that nanobodies are effective tools for stabilizing agonist-bound active states of GPCRs. Building on this technology, we have developed a nanobody-enabled fragment screening approach to explore new chemical space for the development of drugs targeting GPCRs. Our approach has the advantage over other methods in that we can screen fragments that exclusively bind to particular functional conformations of the receptor, allowing us to triage our fragments according to efficacy profile and potency from a single biophysical assay.
11:20 Targeting Low-Druggability Bromodomains (e.g. BAZ2B): Fragment-Based Screening and Inhibitor Design
Fleur Ferguson, Ph.D. Student, Laboratory of Christopher Abell, Department of Chemistry, University of Cambridge
Bromodomain-containing proteins play important roles in transcriptional regulation and disease. The BET bromodomains have been validated as therapeutic targets through development of chemical probes, however many others remain untargeted. The BAZ2B bromodomain is predicted to be the least druggable. We have used fragment-based screening to discover and characterize highly ligand-efficient hits with novel scaffolds. We solved crystal structures of fragments bound to BAZ2B and used structure-based design to optimize and merge the fragments.
11:50 A Robust Solution for Accurate Binding Energy Predictions Using Free Energy Perturbation
Woody Sherman,Ph.D., Vice President, Applications Science, Schrödinger
The accurate prediction of relative binding free energies for compounds within a congeneric series has long been a primary objective for the field of computer-aided drug design. However, the application of rigorous free energy simulations has proven to be unsuccessful in industry due to several factors, including inadequate force fields, insufficient sampling, and laborious simulation setup that challenges even the most experienced modelers. Here, we present our recent developments using molecular dynamics free energy perturbation (FEP) and describe how we have addressed the primary limitations that have hindered the success of FEP in drug discovery. We present results for a large validation set that spans hundreds of ligands across many target families and highlight how FEP can be used to reduce costs and speed drug discovery.
12:20 pm Walk and Talk Luncheon in the Exhibit Hall with Poster Viewing (last chance for viewing)
1:25 Chairperson’s Remarks
Gregg Siegal, Ph.D., CEO, ZoBio
1:30 Featured Presentation: Fragment-Based Discovery of BACE Inhibitors for Alzheimer’s Disease
Andrew Stamford, Ph.D., Executive Director, Medicinal Chemistry, Merck
A fragment screening approach leading to the discovery of the BACE inhibitor MK-8931 currently in clinical trials for the treatment of Alzheimer’s disease will be described. This presentation will discuss the discovery of fragments binding to the active site of the aspartyl protease BACE1 by HSQC NMR screening and the molecular design principles applied to the triaging and optimization of these fragments facilitated by X-ray crystallography-driven structure-based design.
2:00 Fragment Success Story: Case Study of an HCV Drug Candidate
Francisco X. Talamas, Ph.D., former Associate Director and Head, Virology Chemistry, F. Hoffmann-La Roche, Inc.
In this talk, the approaches used to design fragments that bind to the HCV Polymerase NS5B and the process used to select the starting point for our lead expansion efforts will be presented. Also, it will be elaborated upon how structure-based design was used to increase the affinity of the fragment to single digit nanomolar potency. During the optimization process, several liabilities were addressed allowing us to identify a candidate for clinical development.
2:30 Exploiting New Crystal Structure of Human Soluble Adenylate Cyclase for the Identification of Novel Allosteric Inhibitors through Fragment-Based Drug Discovery
Valerio Berdini, Ph.D., Associate Director, Computational Chemistry, Astex Pharmaceutical
I present a series of fragment inhibitors we identified based on the crystal structure of human adenylate cyclase (AC), which we were the first to crystallize. AC catalyzes the synthesis of a second messenger, cAMP. The crystal structure of AC revealed a pseudo-symmetrical arrangement of two catalytic domains with a single competent active site and a novel discrete bicarbonate binding pocket. Our fragments bind the bicarbonate pocket and have been optimized to allow a high level of flexibility of AC’s active and regulatory sites.
3:00 Fragment-Based Approach toward Lactate Dehydrogenase A (LDHA) Inhibitors
Mark Elban, Ph.D., Investigator, CSC Chemistry, RD Platform Technology & Science, GlaxoSmithKline
A fragment-based approach was used to identify a unique series of LDHA inhibitors with good ligand efficiencies. Subsequent optimization delivered a novel lead series with LDHA cellular activity of 10 μM, selectivity against LDHB, and good physicochemical properties. The overall strategy of identification and optimization, lessons learned, and some guiding principles of the FBDD effort will be presented in the context of the discovery of a fragment-derived lead series for the inhibition of LDHA.
3:30 Close of Conference
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