Finding new drug leads for medical conditions with unmet solutions is one of the biggest hurdles in recent drug discovery as the ‘obvious’ drug candidates have already been found. Plus, there are more molecular targets to develop new drugs against thanks to the rapid pace of medical research. Many of these new molecular targets are more complex, such as protein-protein interactions (PPIs) or protein-nucleic acid complexes and move ‘drug hunters’ into less explored chemical space from which to find or design appropriate lead compounds. Luckily, synthetic chemistry and other innovations have expanded the chemical space new drug leads can occupy while still fitting the properties of a ‘good drug’. Join fellow discovery chemists and biologists at the Lead Generation Strategies conference to review the various advances and strategies for finding and creating novel drug leads in today’s expanded chemical and molecular universe.

Final Agenda

Monday, September 16

1:00 pm Pre-Conference Short Course Registration (America Foyer)
Click here for details on short courses offered.

Tuesday, September 17

7:00 am Registration Open and Morning Coffee (America Foyer)

Progressing From Target Hits To Drug Leads
ESSEX south

8:00 Organizer's Welcome Remarks

8:05 Chairperson’s Opening Remarks

Robert D. Mazzola, PhD, Director, Chemical Research, Merck Research Labs

8:10 FEATURED PRESENTATION: Interplay between Lead Generation and Target Validation in AbbVie Early Chemistry: A Wild-Type Isocitrate Dehydrogenase 1 Case Study

J. Brad Shotwell, PhD, Senior Principal Scientist, Tool and Lead Generation Chemistry Group Leader, AbbVie

Inhibition of wild type isocitrate dehydrogenase 1 (IDH1), a key source of cytosolic NADPH under conditions of cellular stress, represents an inroad for treatment of VHL-null mutant renal cell carcinomas. We will summarize AbbVie’s IDH1 lead-finding activities as they inform both best practices for an integrated hit confirmation approach and the critical interplay between small molecule lead generation and the pharmacological testing of novel target hypotheses.

8:40 Exploiting Pilot Screen Hits to Pressure-Test HTS Screening Triage Funnels

Michael Finley, PhD, Principal Scientist, Screening, Discovery Sciences, Janssen R&D

High-throughput screening (HTS) of small molecule libraries requires careful consideration of potential off-target mechanisms that may contribute to false positives or mask identification of on-target active compounds. Employing a pilot screen of representative chemotypes of the larger collection provides a means to pressure test a triage strategy with initial hits. We illustrate several examples in which pilot data were used to identify and address gaps in HTS triage.

9:10 Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery

Jonas V. Schaefer, PhD, Laboratory Head, Encoded Library Technologies, Novartis Institutes for Biomedical Research, Chemical Biology & Therapeutics (CBT), Novartis Pharma AG

The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with the current compound collections is proving increasingly difficult. Encoded library technologies allow for the rapid exploration of a large chemical space for the identification of ligands for such targets. In the presentation, we will discuss how we apply these platforms in our research, including how we narrow the myriad of hits to a few leads, and why we believe it is beneficial to run both pipelines in-house.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:25 Phenotypic Screening Approaches to ALS

Dean G. Brown, PhD, Director, External Chemistry, Hit Discovery, Discovery Sciences, IMED Biotech Unit, AstraZeneca

Amyotrophic lateral sclerosis (ALS) disease has been linked to certain genes and proteins such as repeat G4C2 expansions in the C9ORF72 gene leading to translation of poly-PR proteins and mutant FUS which are toxic and undergoaberrant folding, translation, aggregation or localization.  We will discuss the output of phenotypic screens on these proteins using a yeast strain in a drug-pump deletion background and efforts towards target deconvolution.

10:55 Phenotypic Screening and Chemical Biology Strategies to Identify Mechanisms that Regulate Brain Apolipoprotein E Levels

Martin Pettersson, PhD, Research Fellow, Internal Medicine & Medicinal Chemistry, Pfizer

Apolipoprotein E (ApoE) is a 34 kDa protein that functions as a transporter of cholesterol and phospholipids in both the brain and the periphery. In the brain, it is produced primarily by astro-cytes, and plays an important role in neuronal repair, synaptogenesis, and clearance of neurotoxic amyloid β peptides. This presentation will describe phenotypic screening approaches to identify compounds that regulate ApoE secretion. Chemical biology strategies to elucidate mechanism of action will also be discussed.

11:25 CryoEM Applications for Drug Discovery

Seungil Han, PhD, Cryo-EM Lab Head, Structural & Molecular Sciences, Pfizer Global R&D

Since the introduction of direct electron detectors, the resolution and range of biological molecules amenable to single particle cryo-EM have significantly widened. The prospects of studying protein-ligand interactions of large macromolecular complexes such as ribosome, viral glycoprotein complexes, ion-channels, gamma-secretase etc. without having to generate single crystal, are definitely appealing. We have started to work on several targets to support the discovery of new drugs and vaccines. I will describe the applications of cryo-EM and progresses we have made.  

11:55 Preclinical Approaches to Develop Treatment for Tinnitus

Sylvie Pucheu, CSO, CILcare

Tinnitus is usually perceived as an intermittent or continuous sound. There are many mechanisms inducing tinnitus (acoustic trauma, drug intake, oxidative stress, inflammation), for which there are no approved drugs. This is why CILcare proposes preclinical approaches to help pharmaceutical companies develop new therapies to prevent and treat tinnitus.

12:10 pm Deep Learning Applied to de novo Drug Design

Yann Gaston-Mathé, CEO, Iktos

Simultaneous optimization of multiple objectives is a major challenge in drug discovery. We present the application of Iktos’ AI technology to a complex MPO challenge in a real-life lead optimization project and show that the technology is capable of generating compounds matching all the objectives of the target product profile.

12:25 Session Break

12:35 Luncheon Presentation: Grating-Coupled Interferometry’s Integration into Leadxpro’s Structure-Based Drug Discovery Pipeline

Nicolas Bocquet, PhD, Principal Scientist, leadXpro AG
LeadXpro is a world-class structure based lead (small molecules and biologics) discovery company focusing on challenging membrane protein drug targets, including G-protein coupled receptors (GPCRs), ion channels and transporters. With access to state-of-the-art facilities for structure determination, incluiding the SwissFEL and a single particle cryo-EM system, leadXpro uses the Grating-Coupled Interferometry (GCI) technology to characterize in depth ligand interactions to transmembrane proteins, a significant challenge in the drug discovery “gene-to-lead” process.

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing

Covalent Fragments As Drug Discovery Tools
ESSEX SOUTH

1:50 Chairperson’s Remarks

Beth Knapp-Reed, PhD, Scientific Leader, NCE-MD Medicinal Chemistry, R&D

Platform Technology & Science, GSK

1:55 Use of Chemotype Evolution to Discover Novel, Potent, Irreversible Inhibitors of the Oncogenic G12C Mutant Form of k-RAS

Dan Erlanson, PhD, Co-Founder, Carmot Therapeutics

The protein KRAS has been intensively studied as an oncology target. This presentation will demonstrate how a powerful lead discovery technology, Chemotype Evolution, along with medicinal chemistry and structure-based drug design, were combined to discover novel, irreversible small molecule inhibitors of the oncogenic G12C mutant form of KRAS with potent biochemical and cell-based activity.

2:25 Reactive-Cysteine Profiling for Covalent Ligand Discovery

Eranthie Weerapana, PhD, Associate Professor, Department of Chemistry, Boston College

Reactive and functional cysteine residues provide ideal anchors for covalent ligands. This presentation will focus on the application of a chemical-proteomic technology, known as isoTOP-ABPP, to identify functional cysteines, and monitor proteome-wide selectivity of cysteine-targeted ligands.

2:55 Poster Spotlights
Fragment-Based Molecular Discovery Approach to RAGE Inhibitors

Natalia Kozlyuk, PhD, Postdoctoral Researcher, Structural Biology, Walter Chazin Laboratory, Vanderbilt University

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:05 Covalent Fragments Technology for Drug Lead Generation: Past, Present, and Future

Alexander Statsyuk, PhD, Assistant Professor, Department of Pharmacological and Pharmaceutical Sciences, University of Houston

Covalent fragments is a new lead generation technology, which rests on principles of covalent drug design and fragment-based drug discovery. The main advantage of covalent fragments relative to reversible fragments is that they have enhanced potency and that crystal structures of covalent fragments bound to protein targets can readily be obtained. I will talk about the use of this technology to discover E3 ligase inhibitors and the technology’s future applications in target-based and phenotypic screens.

4:35 Applying Covalent Fragment Approaches to E3 Ligase Inhibitor Discovery

Katrin Rittinger, PhD, Professor, Molecular Structure of Cell Signaling, The Francis Crick Institute, UK

Protein ubiquitination is a critical mechanism to regulate almost all biological processes and defects in the ubiquitin system that are associated with many diseases. However, only a limited number of inhibitors against enzymes of the ubiquitin system are available. I will present a fragment-based covalent ligand screening approach to identify inhibitors of thioester-forming E3 ubiquitin ligases and describe the structure-based development of an inhibitor specific for the RBR ligase HOIP.

Essex Ballroom

5:05 Interactive Breakout Discussion Groups - View All Breakouts

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic.

Integrating FBLD with Other Screening Methods

Moderator: Robert D. Mazzola, PhD, Director, Chemical Research, Merck Research Labs

• Fragment screens vs. HTS vs. DNA-Encoded Libraries (DEL)? Or combos?
• Prosecuting hits: Use separate teams of chemists? Collect data simultaneously?
• Sharing examples/lessons learned

New Biophysical Technologies

Moderator: Anup Upadhyay, PhD, Senior Scientist III, Drug Discovery Science & Technology, AbbVie  

• Biophysical techniques for protein conformational plasticity and hydrodynamic properties, e.g., microscale thermophoresis (MST), second harmonic generation (SHG)
• ‘Toolbox’ biophysical techniques: Which are most popular? Which to use for which applications?
• Correlating results from various biophysical approaches: Identifying and validating true hits

DNA-Encoded Libraries

Moderators: Svetlana Belyanskaya, PhD, Scientific Leader, Encoded Library Technologies, R&D Platform Technology & Science, GlaxoSmithKline Boston
NEW: Chris Phelps, PhD, Manager, R&D Platform Technology & Science, GlaxoSmithKline Boston

• Different types/approaches (i.e., DNA recorded, DNA templated libraries)
• Current constraints on DNA-Encoded Libraries (DNA compatible chemistry, library diversity, selection methods)
• Applications/target classes

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (America Ballroom)

7:10 Close of Day

Wednesday, September 18

7:30 am Registration Open and Morning Coffee (America Foyer)

Fragment-Based And Orthogonal Approaches
ESSEX SOUTH

8:00 Chairperson’s Remarks

J. Brad Shotwell, PhD, Senior Principal Scientist, Tool and Lead Generation

Chemistry Group Leader, AbbVie

8:05 Fragment Screening to Assess Target Ligandability

Fredrik Edfeldt, PhD, Associate Principal Scientist, Discovery Sciences, R&D Biopharmaceuticals, AstraZeneca, Gothenburg, Sweden

Evaluating the ligandability, or chemical tractability, of a protein target is critical when defining hit-finding strategies or to prioritize amongst potential targets. Fragment screening has emerged as a useful approach for this purpose. We demonstrate that thermal shift assays can be used as a simple and generic biophysical method to assess target ligandability. We have applied the method to a set of proteins and show that the assessment is predictive for the success of HTS.

8:35 Fragment-Based Approach to Lactate Dehydrogenase A (LDHA) Inhibitors

Beth Knapp-Reed, PhD, Scientific Leader, NCE-MD Medicinal Chemistry, R&D Platform Technology & Science, GSK

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 identifi-cation 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.

9:05 CDH and Polipa: Novel Approaches to Overcome Target Expression Challenges for FBDD

Daniel Hothersall, Senior Assay Development Scientist, Domainex Ltd.

Domainex is opening up new frontiers in fragment-based drug design. Our Combinatorial Domain Hunting technology is a proven, high throughput method for unlocking challenging targets for structural elucidation. PoliPa is a new approach to the solubilisation of membrane targets without the use of detergents or the need to resort to stabilising mutations. Our talk will discuss the application of these technologies to aid FBDD, citing a number of case studies.

9:35 Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:20 Fragment-Based Discovery and Characterization of ERK1/2 Inhibitors

Puja Pathuri, PhD, Associate Director, Molecular Sciences, Astex Pharmaceuticals

Using a fragment-based campaign and multiple screening methods, including high throughput crystallography and biophysical assays, we identified and developed novel, orally bioavailable inhibitors of ERK1/2 – key components of the Ras signaling pathway in cancer cells. The inhibitors elicit a similar conformational change to currently available inhibitors but also modulate phosphorylation of ERK. Our series of pERK modulating ERK1/2 inhibitors went through progressive rounds of structure-guided optimization and iterative optimizations. The screening cascade included measurement of pRSK levels and anti-proliferative activity in ras and BRAF mutant cells.

10:50 Drug Discovery Using DNA-Encoded Chemical Libraries

Rachael Jetson, PhD, Senior Research Scientist, Lead Discovery, X-Chem Pharmaceuticals

X-Chem’s DNA-encoded chemistry platform provides a method to simultaneously interrogate a diverse chemical library against many targets to identify lead compounds. This presentation will describe the X-Chem platform and highlight case studies leading to the discovery of novel covalent and non-covalent chemical equity to multiple targets.

11:20 Enjoy Lunch on Your Own

11:20 Conference Registration for Programs 1B-7B

Essex Ballroom

PLENARY KEYNOTE PROGRAM
Click here for full abstracts.

12:20 pm Event Chairperson’s Opening Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute

12:30 Plenary Keynote Introduction

Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd

12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells

David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University

1:20 PROTACs: Past, Present, and Future

Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University

2:00 Close of Plenary Keynote Program

2:00 Dessert Break in the Exhibit Hall with Poster Viewing (America Ballroom)

2:45 Close of Lead Generation Strategies Conference