8:55 am Chair’s Opening Remarks

To Dimer or Not to Dimer

9:00 am Overcoming the Challenge of GPCR Heteromerizations to Discover Novel Drug Targets & Develop New Therapeutics with Higher Selectivity

9:30 am Panel Discussion: Debating the Relevance of GPCR Dimers and Whether Signaling through GPCR Heterodimers is Pharmacologically Relevant

Synopsis

  • We acknowledge dimerization occurs, but what is the pharmacological relevance?
  • Can you selectively target GPCR heterodimers using ligands that bind both dimers or monomers?
  • How can we leverage experimental data on dimerization, computationally?

Peeling Back the Unknowns in the Orphan Drug / Dark Target Space to Create Druggable Targets

10:15 am Reviewing What we know about Orphan GPCR Targets

  • Bryan Roth Professor of Pharmacology, UNC School of Medicine

Synopsis

*Virtual

  • Outlining why so little is know about this class of GPCR targets
  • Leveraging orphan and understudied GPCRS (oGPCRs) which represent potentially transformative targets for drug discovery
  • Highlighting the new open-source technologies to discover and validate drugs at oGPCRs

10:45 am

Morning Break & Networking

11:15 am Unlocking the Therapeutic Potential of Previously Undruggable Peptidergic GPCRs

Synopsis

  • Orion’s platform introduces efficiencies to GPCR discovery
  • Developing novel molecules with optimized characteristics for drugging peptidergic GPCRs
  • Diversified portfolio of preclinical and clinical programs
  • AI integration for data-driven pipeline expansion

11:45 am Expanding the Availability of Druggable GPCRs

  • Paul A. Insel M.D., Distinguished Professor of Pharmacology and Medicine, University of California San Diego

Synopsis

  • Spearheading novel GPCR drug discovery through identifying and validating the proton-sensing GPCRs
  • Spotlighting proton-sensing GPCRs as possible therapeutic targets in cancer
  • Realizing the potential for translation into proton-sensing GPCR – targeted drug development

Elevating Bias Signaling & Allosteric Modulation Understanding

12:15 pm Spotlight: GPCR Allosteric Modulators in Drug Discovery

  • Kate Lansu Senior Scientist, Eli Lilly & Company

Synopsis

  • Reviewing the literature and rationale behind allosteric modulation GPCR research and development
  • Detailing methods used to illuminate structural changes following allosteric modulation
  • What’s next? A look towards translation to the clinic

12:45 pm

Lunch

1:45 pm Functional Diversification of Signaling by GPCR Localization

Synopsis

  • A new paradigm: GPCRs can signal from intracellular membranes
  • Characterizing the functional outputs of compartmentalized GPCR signaling
  • Unveiling insights into mechanisms regulating the spatial bias of receptor activity

2:15 pm Mechanisms of the Investigational Antipsychotic, KarXT

Synopsis

  • Unveiling KarXT (xanomeline + trospium); an oral, investigational M1/M4-preferring muscarinic agonist in development for the treatment of psychiatric and neurological conditions, including schizophrenia and psychosis in Alzheimer’s disease
  • Harnessing research which indicates that activity at M1 and M4 receptors indirectly affects dopamine neurotransmission in brain regions involved in mediating symptoms of serious mental illness, such as psychosis in Alzheimer’s disease, as well as the positive, negative, and cognitive symptoms of schizophrenia
  • Centrally active xanomeline has demonstrated unique agonistic pharmacology at the muscarinic receptors including persistent binding and functional selectivity based on cryo-EM, molecular dynamics, and mutagenesis experiments

2:45 pm Approaches to Characterize Biased Agonists in Early Phase Drug Development

Synopsis

  • Reviewing the literature and rationale behind bias signaling in GPCR research and development
  • Detailing methods used to illuminate bias in downstream pathways
  • Linking signaling bias to different physiological outcomes

3:15 pm

Afternoon Break & Networking

3:45 pm Inhibition of Acid Sensing by Allosteric Modulation of GPR65 Normalises Gene Expression in Primary Macrophages, Increases Natural Killer Cell Infiltration in Subcutaneous MC38 Tumors, and Restricts Tumor Growth

Synopsis

  • Displaying how high frequencies of Tumor-Associated Macrophages (TAMs) are associated with poor patient prognosis
    • Leveraging the fact acidic conditions of the tumor microenvironment suppress macrophage immune function and support a pro-tumor TAM state
  • Demonstrating how TAMs sense low pH through G-Protein Coupled Receptor 65 (GPR65)
  • Utilizing Pathios compounds to inhibit GPR65 sensing of pH in vitro with excellent potencies, resulting in profound gene expression changes, and demonstrate therapeutic benefit in the MC38 Tumor Growth Inhibition model in vivo, elevating the frequency of tumor-infiltrating Natural Killer cells

4:15 pm Approaches to Characterize Allosteric Modulation in Drug Development [case study]

Synopsis

  • Reviewing the literature and rationale behind bias signaling in GPCR research and development
  • Detailing methods used to illuminate bias in downstream pathways
  • What’s next? A look towards translation to the clinic

4:45 pm Chair’s Closing Remarks

4:50 pm End of Conference