SC10: Introduction to Allosteric Modulators and Biased Ligands of GPCRs

Wednesday, September 23, 7:00-9:30 pm

Allosteric modulators, pathway-biased ligands, and heteromer-biased ligands represent novel therapeutic approaches for achieving more selective actions with regards to G protein-coupled receptors (GPCRs). However the identification and characterization of such compounds can be challenging due in part to ‘context-dependent phenomena’. Aimed at scientists working on GPCRs this course will provide information on the identification and validation of allosteric, pathway-biased, and heteromer-biased drugs including emerging screening approaches, practical tips and tools for identification and validation, and the structural basis underlying such drugs.

Instructors:

Annette Gilchrist, Ph.D., Associate Professor, Pharmaceutical Sciences, Midwestern University

Karen Gregory, Ph.D., Laboratory Head, Family C GPCR Division,  Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Australia

Kevin Pfleger, Ph.D., Associate Professor, Molecular Endocrinology & Pharmacology, Harry Perkins Institute of Medical Research and The University of Western Australia, Australia  

Introduction to Allosterism and Biased Signaling (Annette, 30 min)

• Definitions, conceptual and practical explanations of allosteric modulators and pathway biased ligands and their relationships to one another
• Receptor structure with an emphasis on known allosteric binding sites
• Current status of the field (allosteric and biased ligands in development or on the market)

Arrestin-biased signaling Screening and Validating Allosteric and Biased Ligands (Karen, 45 min.)

• Screening, quantification and validation of allosteric and biased ligands
• Differentiating allosteric v. bitopic v. orthosteric ligands
• Complexities and challenges for discovery:
• the problem with potency
• molecular switches
• probe dependence
• observational versus ligand bias

Receptor heteromers (Kevin, 30 min)

• Heteromers as allosteric modulators
• Heteromer-biased signaling
• Approaches to specifically investigate receptor heteromerization

Q&A (15 min)

Instructor Biographies:

 Annette Gilchrist, Ph.D., Associate Professor, Pharmaceutical Sciences, Midwestern University

Currently an Associate Professor with Midwestern University, Dr. Gilchrist works on allosteric and/or biased modulators for a number of different GPCRs including PAR1, CCR1, and FFAR2. She also serves as the Senior Online Editor for British Journal of Pharmacology and British Journal of Clinical Pharmacology. In addition to editing the book “GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions” published by John Wiley and Sons she has written chapters on G protein signaling and CCR1 antagonists. Currently she is working with Dr. Paula Stern as a guest editor for Frontiers in Endocrinology for a themed issue on “Chemokines and Bone”. Previously, she was with Cue Biotech and Caden Biosciences, companies she co-founded that focused on GPCRs and used a novel approach to identify allosteric compounds based on their ability to modulate GPCR/G protein coupling (US Patent Numbers 7,208,279 and 7,294,472). Prior to that Dr. Gilchrist worked as an Assistant Research Professor in the Department of Molecular Pharmacology & Biological Chemistry at Northwestern University where she developed a set of unique tools known as minigene vectors (US Patent Number 6,559,128). Minigene vectors allow one to dissect out the G protein that mediates a given physiological function and they have been widely adopted by researchers around the world. Preceding that Dr. Gilchrist was a postdoctoral fellow with Dr. Heidi Hamm. In this setting, she identified high affinity peptides that mimic the C-terminus of Ga, and were later used for crystallization of rhodopsin. Dr. Gilchrist’s work on GPCRs began with her graduate studies in which she studied signaling of chemokine receptors through tyrosine kinases and phosphatases. Dr. Gilchrist has a PhD in Immunology from the University of Connecticut Health Center and a MS in Biochemistry from the University of Connecticut.

 Karen Gregory, Ph.D., Laboratory Head, Family C GPCR Division,  Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Australia

Karen J Gregory is an early career researcher with a strong expertise in the molecular pharmacology of G protein-coupled receptors (GPCRs). She currently co-heads the Family C GPCR division in Drug Discovery Biology at Monash Institute of Pharmaceutical Sciences, Monash University. Her research efforts are primarily directed on the structural and molecular pharmacology of metabotropic glutamate receptors, with a particular focus on allosteric modulators and biased pharmacology.
Before returning to Australia, Dr Gregory spent a highly successful 4-year postdoctoral period under the mentorship of Prof. Jeff Conn at Vanderbilt University Medical Center, Nashville, TN, USA. Dr Gregory received her PhD in pharmacology from Monash University, Australia in 2009 working on allosteric modulation of muscarinic acetylcholine receptors under the supervision of Profs. Patrick Sexton and Arthur Christopoulos.

 Kevin Pfleger, Ph.D., Associate Professor, Molecular Endocrinology & Pharmacology, Harry Perkins Institute of Medical Research and The University of Western Australia, Australia

Associate Professor Kevin Pfleger is Head of Molecular Endocrinology and Pharmacology at the Harry Perkins Institute of Medical Research and the Centre for Medical Research, The University of Western Australia. He is a National Health and Medical Research Council (NHMRC) RD Wright Biomedical Research Fellow (Level 2), as well as being the Chief Scientific Advisor of Dimerix Bioscience, a spin-out company from the Perkins and The University of Western Australia. He was awarded his MA and PhD from Cambridge and Edinburgh Universities respectively, and relocated to Western Australia in October 2002. He was a NHMRC Peter Doherty Research Fellow from 2005 to 2008 and an Australian Research Council (ARC) Future Fellow from 2011 to 2014. He was named Western Australian Young Scientist of the Year 2009 and his work featured as one of the NHMRC 10 of the Best Research Projects 2010. In 2011, he was awarded the Australian Museum 3M Eureka Prize for Emerging Leader in Science and in 2012 he won The Endocrine Society Early Investigators Award supported by Amgen and the Western Australia Young Tall Poppy Science Award. Most recently, Associate Professor Pfleger has been honoured with the Endocrine Society of Australia's Mid-Career Research Award for 2014.

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