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G-Protein Coupled Receptors (GPCRs) because of their role in many medically-relevant pathways, are attractive targets for pharmacological modulation. Though many GPCR-targeted drugs are on the market, the complexities of GPCR signaling still make drug discovery against GPCRs a challenging endeavor. This meeting will cover efforts in discovering and developing compounds such as antibodies, allosteric modulators and biased agonists that modulate in non-traditional ways. These ligands have the potential of more precisely controlling receptor signaling and ultimately therapeutic effects. Join fellow drug discovery colleagues for the first ever meeting track at CHI’s World Preclinical Congress event focused on GPCRs.

Final Agenda


Wednesday, June 10

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks

Conrad Cowan, Ph.D., Head, Biology, Trevena


Krzysztof PalczewskiKrzysztof Palczewski, Ph.D., Professor and Chair, Department of Pharmacology, School of Medicine, Case Western Reserve University

A systems pharmacology approach employs signaling pathways to enhance rational therapeutic strategies for treating complex disorders/diseases. Our proposal for systems pharmacology starts with a quantitative transcriptome analysis not only of cells, but also of tissues and organs of interest. Next, a reliable animal model that recapitulates the human condition(s) must be available to investigate combinations of drugs that act on one or several network pathways to select those most suited for human trials.

8:35 Novel Strategies for Biasing GPCR Signaling

Jeffrey Benovic Jeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry and Molecular Biology, Thomas Jefferson University

G protein-coupled receptors (GPCRs) interact with three families of proteins in a ligand-dependent manner: heterotrimeric G proteins, GPCR kinases and arrestins. These interactions play an essential role in regulating GPCR signaling, trafficking and degradation. In this presentation, I will highlight recent strategies used to bias GPCR signaling with an emphasis on the use of lipidated GPCR peptides (pepducins) to promote GPCR interaction with selective downstream targets.

9:05 Translating Bias: from the Bench to the Clinic

Conrad Cowan, Ph.D., Head of Biology, Trevena

Biased ligands targeting GPCRs can selectively stimulate or inhibit distinct downstream signaling pathways, and may provide improved therapeutic efficacy and/or reduced side effects relative to unbiased ligands. Preclinical and clinical data will be presented on two of our most advanced biased ligand programs, one a β-arrestin-biased ligand of the Angiotensin type II type 1 receptor for acute heart failure and the other a G protein-biased ligand of the μ-opioid receptor for pain.

9:35 Biased Agonists for Dopamine D2 Receptors: Novel Antipsychotic Drugs?

John A. Allen, Ph.D., Principal Scientist, Neuroscience, Pfizer

We have generated biased ligands for various Dopamine receptors to test if selectively engaging signaling pathways will provide new therapeutics for neurological diseases. Using the Dopamine D2 receptor as example, I will describe our effort generating agonists that exclusively activate D2-Gi/o or D2-Beta-arrestin signaling. Agonists that enabled arrestin engagement, but not Gi/o activation, induced prolonged ERK signaling and showed robust antipsychotic activity with reduced motoric side-effects in rodent models.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing


10:50 Ligand Bias in the Interaction of Muscarinic M3 Receptor with a Regulator of G Protein Signaling (RGS) Complex, Gβ5-RGS7

Vladlen Z. Slepak, Ph.D., Professor, Molecular and Cellular Pharmacology, University of Miami

The G protein β subunit Gβ5 forms obligatory heterodimers with R7 family RGS proteins. Gβ5-RGS7 can directly bind to M3R and has a dual effect: attenuates the Ca2+ release from stores, while augmenting Ca2+ influx across the plasma membrane. M3R-induced insulin secretion was practically eliminated by Gβ5 knockout, consistent with the idea that Gβ5-RGS7 is necessary for Ca2+ influx in beta cells. Responses to oxotremorine-M were insensitive to Gβ5-RGS7 while pilocarpine-induced signals were particularly strongly inhibited.

11:20 Polypharmacology and Multi-Targeted Directed Ligands (MTDL) for GPCRs

Ronan BureauRonan Bureau, Ph.D., Professor, Molecular Modelling, CERMN, University of Caen, France

The design of new type of ligands (MTDL) able to modulate several biological pathways involved in a specific disease represent a particular challenge. The presentation will concern our last results for alzheimer disease implying 5-HT4 and H3 receptors.

Schrodinger11:50 Structure-based Computational Approaches for the Identification and Optimization of GPCR Ligands

Beuming_ThijsThijs Beuming, Ph.D., Research Leader, Applications Science, Schrödinger

We present computational strategies for GPCR lead identification and optimization, covering a broad range of applicability. First, we developed a customizable modeling protocol to optimize homology models, as well as a probabilistic model to boost virtual screening enrichment by considering explicit water molecules in the GPCR binding site. For optimizing potency, we validated and applied all-atom MD-based free energy calculations (FEP) to a variety of GPCR targets. Advanced hydration site analysis (WaterMap) was used to explain an unintuitive SAR within a series of triazolylpurine analogues.

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:00 Refreshment Break in the Exhibit Hall with Poster Viewing


1:30 Chairperson’s Remarks

Jeffrey L. Benovic, Ph.D., Professor and Chair, Department of Biochemistry and Molecular Biology, Thomas Jefferson University

1:35 Targeting GPCRs with Monoclonal Antibodies

Trevor WilkinsonTrevor Wilkinson, Ph.D., Associate Director, Protein Sciences, Antibody Discovery and Protein Engineering, MedImmune

G-protein coupled receptors represent a challenging target class for the isolation and optimization of therapeutic biologics. We have used a combination of immunization and phage display to isolate functional antagonistic antibodies targeting a chemokine receptor and a formyl-peptide receptor which will be presented as case studies. We also describe how combinatorial mutagenesis approaches have been used to make significant improvements to both affinity and species cross-reactivity of a lead molecule and demonstrate that the optimised antibodies show significantly increased potency in cellular disease assays.

2:05 Using StaR Proteins as Antigens to Generate Antibodies to GPCRs

Ali Jazayeri, Ph.D., Head, Engineering, Heptares

GPCRs represent excellent antibody targets given their central role in the pathology of many diseases and cell surface location. However GPCRs make poor antigens due to their conformational flexibility, low expression levels, inherent instability and hydrophobic nature. Using protein engineering approaches we create conformationally stabilised receptors (StaRs) that can be purified to high purity and homogeneity with enhanced half-life. StaRs allow generation of high quality antigens that can be used to raise functional antibodies.

2:35 Nanobodies as Tools for Probing GPCR Structure and Function

Andrew C. Kruse, Ph.D., Assistant Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

Heavy-chain only camelid antibodies (nanobodies) have emerged as powerful and versatile tools in GPCR structural biology. Their use has enabled important insights into the structural basis for GPCR activation and allosteric regulation by small molecule ligands, including active-state structures of adrenergic and muscarinic receptors. I will discuss the methods used for identifying conformationally selective nanobodies, and the insights they have offered into the molecular details of GPCR activation and allostery.

3:05 Modulating GPCR Signaling using Conformationally Selective Nanobodies

Dean Staus, Ph.D., Robert J. Lefkowitz Lab, Postdoctoral Fellow, Department of Medicine, Duke University Medical Center, Howard Hughes Medical Institute

The signaling cascades induced by ligand binding to a GPCR are mediated by stabilization of specific receptor conformations which leads to the coupling and activation of G-protein and β-arrestin. A total of 18 conformationally selective single domain Camelid antibodies (nanobodies) were tested for their ability to modulate beta-2-adrenergic receptor dependent signaling. When expressed intracellularly (intrabodies), these nanobodies inhibited G protein activation, G protein–coupled receptor kinase (GRK)–mediated receptor phosphorylation, β-arrestin recruitment, and receptor internalization to varying extents.

3:35 Functional Antibodies for GPCRs

Beayong-Doo-SongByeong Doo Song, Ph.D., President, Scripps Korea Antibody Institute

GPCRs have not been easy targets to obtain functional antibodies for because traditional antibody screening requires target preparation. We developed a new method to construct an expandable spatially addressed Fv antibody library from combination of purified proteins, which enables screening of individual antibodies using cell based assays without target preparation. Direct functional screening method has lead to discovery of novel antibodies for GPCRs.


4:05 Refreshment Break in the Exhibit Hall with Poster Viewing


6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

7:00 Close of Day

Thursday, June 11

7:30 am Interactive Breakout Discussion Groups with Continental Breakfast

Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking. 

TABLE 6: Benefits and Challenges of Label-free Investigations in GPCR Drug Discovery

Moderator: Stephanie Hennen, Ph.D., Senior Scientist, Department of Incretin Biology, Global Research Organization, Novo Nordisk A/S

  • Are such holistic methods useful to identify biased ligands?
  • Can whole cell label-free analyses help to improve in vitro –in vivo translation?
  • Experience by participants: How and where do label-free technologies fit best into drug discovery projects?

TABLE 7: Obtaining and Using GPCR Crystal Structures

Moderator: Andrew C. Kruse, Ph.D., Assistant Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

  • What are the most important unanswered questions in GPCR structural biology?
  • Is GPCR structural information being fully leveraged in drug discovery?
  • How can GPCR structural determination be streamlined for therapeutically important targets?
  • How can we more effectively use antibodies as therapeutics and structural tools for GPCRs?

TABLE 8: Therapeutic Antibodies and GPCRs

Moderator: Trevor Wilkinson, Ph.D., Associate Director, Protein Sciences, Antibody Discovery and Protein Engineering, MedImmune (to be confirmed)

  • GPCR-targeted antibody production challenges and best practices
  • Which GPCRs are most amenable?
  • What are the latest roadblocks?
  • When will next ‘approval’ be and for what?


8:35 Chairperson’s Remarks

Neil Burford, Ph.D., Senior Research Investigator II, Leads Discovery and Optimization, Bristol- Myers Squibb

8:45 Putting a STOP: Structural Visualization of GPCR Desensitization

Arun ShuklaArun Shukla, Ph.D., Professor, Department of Biological Sciences and Bioengineering, Indian Institute of Technology and Wellcome Trust/DBT Indian Alliance Intermediate Fellow

The functions of G-protein coupled receptors (GPCRs) are primarily mediated and modulated by the heterotrimeric G proteins, the G-protein coupled receptor kinases (GRKs), and the β-arrestins. Binding of β-arrestins hinders G protein coupling and leads to receptor desensitization. I will discuss our efforts to understand the structural basis of GPCR-β-arrestin interaction and how this interaction mediates desensitization of GPCRs.

9:15 Cell-Based Label-Free Dynamic Mass Redistribution Assays for Elucidating GPCR-Mediated Signaling

Stephanie Hennen, Ph.D., Senior Scientist, Department of Incretin Biology, Global Research Organization, Novo Nordisk A/S

The majority of techniques currently employed to examine signaling behavior of GPCRs requires artificial labels. In contrast to these classical methods, a number of novel label-free technologies have emerged recently that are competent to resolve receptor activity as integrated cellular response. The present talk will introduce a label-free method based on dynamic mass redistribution and attempt to show the strengths of holistic label-free detection as compared with classical functional assays but also highlight the challenges.

9:45 SPR-based Assays for Ranking and Selecting mAbs Targeting GPCRs

Rick Chu, Ph.D., Associate Director, Clinical Assay Development, Genzyme, a Sanofi Company

Traditionally, membrane protein binding assays rely on utilizing radioactive labeled ligands. In order to simplify membrane protein kinetics binding assay, purified membrane proteins, such as G-protein-coupled receptors (GPCRs), are captured on analytical surfaces and further stabilized by limited chemical crosslinking. This limited chemical crosslinking enables high quality label-free kinetics assays of membrane proteins via the same methods that are conventionally used for soluble proteins.


10:15 A Label-Free, Solution-Based Affinity Assay for Allosteric GPCR Ligand Binding Using Back-Scattering Interferometry

Isaacs_JakeRichard J. Isaacs, Ph.D., Applied Research Supervisor, Molecular Sensing, Inc.

Integral membrane proteins such as GPCRs are critical targets for drug discovery but present a host of challenges to the characterization of their binding affinity for small molecules. Determination of allosteric binding in GPCR targets is especially valuable and extremely challenging information to obtain by established binding assay platforms, but can be addressed through a label-free solution-based direct-binding technology, back-scattering interferometry (BSI).

10:45 Coffee Break in the Exhibit Hall with Poster Viewing


11:30 Positive Allosteric Modulators of Opioid Receptors

Neil Burford, Ph.D., Senior Research Investigator II, Leads Discovery and Optimization, Bristol-Myers Squibb

Opioid receptors are among the most studied GPCRs and are the targets for opiate ligands including morphine, which are key drugs used in the management of pain. However, these opiate ligands also exhibit serious receptor-mediated side effects including tolerance and dependence. The recent discovery of opioid receptor positive allosteric modulators by our lab offers a novel approach for future pain medications because of the potential advantages allosteric ligands have over orthosteric ligands.

12:00 pm mGluR3 PAM as a GDNF-inducer Strategy for the Treatment of Neurodegenerative Disorders

Stephan SchannStephan Schann, Ph.D., Head of Research, Domain Therapeutics

Glial cell line-derived neurotrophic factor (GDNF) is a peptide that previously showed clinical efficacy for the treatment of Parkinson’s disease. mGluR3 constitutes a novel target that could lead to neuroprotection through production of GDNF. This potential was demonstrated with an orthosteric mGluR2/3 agonist and KO mice. Novel small molecules mGluR3 PAMs were recently discovered at Domain. These molecules were characterized in neuroprotection and GDNF production models. Our results show that mGluR3 PAMs shared similar activities with the mGluR3 orthosteric agonist.

12:30 Close of Conference