Lead Generation Strategies

Finding new chemical entities with high drug potential as fast as possible has always been the goal in early drug discovery. Often the process is separated into two steps: ‘hit’ generation which focuses on quickly finding large numbers of compounds with questionable drug potential followed by secondary screens to reveal promising, high-drug potential leads. Recently though the two processes are often combined because of automation and biophysical advances that enable smaller numbers but higher quality drug leads to be found from the start. After the successful launch of CHI’s Lead Generation Strategies conference last year, we return to convene discovery biologists and chemists to share best practices and discuss how to implement new approaches towards faster and higher quality lead generation for drug discovery.

Final Agenda

Choose 2 Short Courses
or 1 Symposium and 2 Conferences/Training Seminars

Thursday, September 27

11:50 am Conference Registration Open (Foyer)

12:20 pm Plenary Keynote Program (Constitution Ballroom)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Fairfax B

2:45 Welcome Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

Joe Patel, PhD, Director, Structural Biology, C4 Therapeutics

2:55 KEYNOTE PRESENTATION: Mechanistic Pharmacology-Driven Lead Discovery

Peter Tummino, PhD, Vice President, Global Head, Lead Discovery, Janssen Research and Development

Decades of effort in small molecule screening has focused on increasing throughput and com-pound library size. Generally, these large efforts have not yielded major advancements in providing quality lead molecules. An alternative approach is to design screening assays that are more disease-relevant, incorporate knowledge from detailed mechanistic studies, and possess multiparametric readouts. This approach, combined application of machine learning to data analysis, may provide a stronger engine for lead ID.

3:25 Do We Need to Change the Definition of Drug-Like Properties?

Michael Shultz, PhD, Associate Director and Group Leader, Cardiovascular and Metabolism Medicinal Chemistry, Novartis Institutes for Biomedical Research


3:55 Integrated Drug Discovery Engine for the Development of the Next-Generation Kinase Inhibitors

Alexis Denis, Head, Discovery Division, Oncodesign

Nanocyclix is a medicinal chemistry technology based on the macrocyclization of small Lead-like molecules. It is a kinase-focused library designed in a chemocentric approach to identify drug-like and selective inhibitors across the kinome. Nanocyclix leads have potential application in several indications: Oncology, Immuno-inflammation and Parkinson disease.

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

5:00 Targeted Degradation Strategies for New Drug Leads

Patel_JJoe Patel, PhD, Director, Structural Biology, C4 Therapeutics

Targeted protein degradation has emerged as an exciting new approach for drug discovery. This talk will provide a brief overview of the technology and how degraders exploit the ubiquitin-proteasome system before describing therapeutic applications of targeted protein degradation to BET bromodomain proteins and to the control of tumor cell-killing by CAR T-cells.

5:30 Encoded Library Technology (ELT): A Platform for Lead Discovery at GSK

Belyanskaya_S_HTLSvetlana Belyanskaya, PhD, Scientific Leader, Encoded Library Technologies, R&D Platform Technology & Science, GSK Boston

DNA Encoded Library Technology is an affinity-based screening platform that is routinely used for lead discovery at GSK. It was successfully applied for discovery of potent and selective inhibitors to multiple challenging targets. The platform has evolved and a quantitative on-DNA binding assay has recently been developed for simultaneous characterization of billions of compounds in the selection. A case study will be presented to illustrate its application for a hit identification program.

6:00 CETSA (Cellular Thermal Shift Assay) HT to Measure Intracellular Target Engagement with the Androgen Receptor

Shaw_JosephJoseph Shaw, PhD, Senior Scientist, Lead Generation, AstraZeneca

CETSA (Cellular Thermal Shift Assay) is an exciting technology increasingly being used to determine in-cell target engagement in early drug discovery campaigns in a label-free and disease relevant manner. We report a new high-throughput CETSA assay for the high value oncology target Androgen Receptor, and demonstrate a novel application of CETSA enabling determination of intracellular binding affinities. Application of high-throughout CETSA technology can guide lead generation campaigns using direct measures of binding to the desired target in cells.

6:30 Dinner Short Course Registration (Foyer)

9:30 Close of Day

Friday, September 28

7:00 am Registration Open

7:30 Interactive Breakfast Breakout Discussion Groups - View Details

Room: Constitution B

Grab a cup of coffee and 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.

Table 12: Degradation-Induced Therapeutics

Moderator: Joe Patel, PhD, Director, Structural Biology, C4 Therapeutics

  • Ubiquitin-mediated protein degradation strategies 
  • Which technique to try first?
  • Hurdles to their therapeutic potential
  • Stories to share?

Table 13: DNA-Encoded Libraries

Co-moderators: Svetlana Belyanskaya, PhD, Scientific Leader, Encoded Library Technologies, R&D Platform Technology & Science, GSK Boston

Ghotas Evindar, PhD, Manager, ELT Chemistry, GSK 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

Fragment-Based Libraries

Moderator: Ashley Adams, PhD, Senior Scientist, Discovery Chemistry and Technology, AbbVie, Inc.

  • Revamping libraries – what have we learned?
  • When to use which type of library?
  • Pros and cons of various commercial libraries 

Biophysical Methods for More Efficient Lead Generation
Fairfax B

8:30 Chairperson’s Remarks

Daniel A. Erlanson, PhD, Co-Founder, Carmot Therapeutics, Inc.

8:35 Novel Approaches in Using NMR and SPR for Fragment Hit Identification and Validation

Anil Padyana, PhD, Associate Director, Structural Biology and Biophysics, Department of Biochemistry, Agios Pharmaceuticals

9:05 AbbVie’s Fragment-Based Drug Design Platform for Tool and Lead Generation

Adams_AAshley Adams, Ph.D., Senior Scientist, Discovery Chemistry and Technology, AbbVie, Inc.

This presentation will cover a recent application of AbbVie’s revamped fragment library featuring an example where a fragment with high fsp3 character was quickly advanced to lead with high BEI, LE, and LipE as well as good oral bioavailability. The unique properties associated with fragments with high sp3 character and some lessons learned on the efficiency of chemistry to iterate 3D fragment hits will also be discussed.

9:35 Solid-State NMR for Peptide Drug Optimization

Su_YongchaoYongchao Su, PhD, Associate Principal Scientist and Head of the Pharmaceutical NMR Lab in Preclinical Sciences, Merck & Co., Inc.

We used solid state (ss) NMR to determine the high-resolution structure of fibrils from a pharmaceutical peptide. This is the first time in pharmaceutical sciences that a high resolution molecular structure of insoluble aggregate of a peptide drug has been determined. The structure enabled us to identify and test residues in the fibril core that lead to backbone rearrangement, which should facilitate optimization of peptide drugs with lower risks of aggregation.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (Grand Ballroom)

10:45 Using Stable Isotope Tracers to Interrogate Pathway Biology and Differentiate Potential Hits

Hatcher_HTLNathan Hatcher, PhD, Principal Scientist, Department of Neuroscience, Movement Disorders and Translational Capabilities, Merck & Co., Inc.

This presentation will consider how to probe biochemical flux via stable isotope tracer methods. Focus will be placed on differentiation of possible lead candidates. Attention will be directed towards cell-based screening efforts; however, we will discuss the potential for translational opportunities using in vivo models. Example problems will be described which consider “classical” metabolic pathways, e.g., glucose flux, as well. We will consider problems regarding protein kinetics.

11:15 New Gas-Phase Tools for the Simultaneous Determination of Protein Complex Structure, Stability and Sequence

Brandon Ruotolo, PhD, Associate Professor, Department of Chemistry, University of Michigan

The next generation of medicines will rely heavily upon our ability to quickly assess the structures and stabilities of large, complex macromolecular machines, as well as the influence of large libraries of conformationally-selective small molecule binders and protein-based biotherapeutics. Such endeavours are nearly insurmountable with current tools. In this presentation, I will discuss recent developments surrounding the activation of gas-phase protein complex ions aimed at bridging this gap in basic technology.

11:45 Every Compound Counts – Virtual Screening and Computer-Aided Drug Design for a More Efficient Route to Drug Discovery

Perrior_Trevor_HTLTrevor Perrior, CSO, Domainex

Domainex clients have seen the benefit of its efficient approach, which significantly increases the speed from drug target to candidate molecule. An important part of this philosophy is the use of computational techniques for the selection of screening libraries, and for the design of compounds during lead optimisation.

12:15 pm Session Break

ZoBio 12:25 Luncheon Presentation:Protein Domain Trapping - Large Scale Protein Engineering Enables Biophysics and Structural Biology in Drug Discovery

Jan Schultz, Director, Business Development, ZoBio

With novel targets the rate limiting step in small molecule drug discovery often becomes the availability of protein in an appropriate, well-behaved form. Standard methods for generating constructs are far too slow and sample only a fraction of the great number of possibilities. ZoBio has developed PDT to screen millions of protein variations for those that express high levels of soluble, well-behaved protein with the desired biological activity. Initial feasibility studies require only 4-6 weeks.

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Biophysical Approaches for Membrane Proteins
Back Bay B

1:55 Chairperson’s Remarks

Brian J. Murphy, PhD, Director, Metabolic Disease Biology, Bristol-Myers Squibb Co.

2:00 Discovery of Small Molecule Protease-Activated Receptor 2 (PAR2) Antagonists Using a Stabilized GPCR, Fragment-Based Lead Generation and DNA-Encoded Library Screening

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

We employed two screening strategies to identify antagonists at protease activated receptor (PAR2), one being a DNA-encoded library screen on PAR2 and the second a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites. These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.

2:30 Integrating Biophysical and Structural Data Provides Comprehensive View of GPCR Function

Eddy_MatthewMatthew Eddy, PhD, Assistant Professor, Department of Chemistry, University of Florida and Affiliated Faculty, National High Magnetic Field Laboratory

3:00 NEW: Nanodiscs for Membrane Protein Drug Discovery Applications

Mahmoud l. Nasr, RPh, PhD, Instructor, Biological Chemistry and Molecular Pharmacology Department. Harvard Medical School

We present a method for manufacturing membrane bilayer nanodiscs encircled by DNA scaffold or covalently circularized Apolipoprotein A1 variants. We are able to extend the size of nanodiscs up to 90 nm in diameter. Furthermore, we demonstrate the potential use of these nanodiscs as model membranes to study virus entry. Finally, we demonstrate the potential use of these newly engineered nanodiscs in GPCR and antiviral drug discovery.

3:30 NEW: Close of Conference

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