Speaker Q&A 

Cambridge Healthtech Institute recently spoke with Dr. Michel Bouvier of Université de Montréal about his insights on GPCRs and where the field is headed in coming years.  Dr. Bouvier is the keynote speaker at the 14th Annual Mastering Medicinal Chemistry- Part 2 which is taking place from June 14-15, 2017 in Boston, MA where he will be delivering his talk on “Exploring the Pluridimensionality of G Protein-Coupled Receptor Signaling Efficacy; Potential Impacts for Drug Discovery”. This conference is being organized as part of the 16th Annual World Preclinical Congress event which runs from June 12-16, 2017 in Boston, MA. 

MichealBouview  Michel Bouvier, Ph.D., Professor/General Director, Biochemistry and Molecular Medicine/Institute for Research in Immunology and Cancer, Université de Montréal

Michel Bouvier holds a B.Sc. in biochemistry (1979) and a Ph.D. in Neurological Sciences (1985) from the Université de Montréal and obtained post-doctoral training (1985-89) at Duke University under the supervision of Dr. R.J. Lefkowitz (Nobel prize Chemistry 2012).  He is professor of Biochemistry and Molecular Medicine at the Faculty of Medicine of the Université de Montréal and principal investigator at the Institute for Research in Immunology and Cancer. Dr. Bouvier is a world-renowned expert in the field of cell signaling and G protein-coupled receptors (GPCR) and made seminal contributions to our understanding of this major class of drug targets. His work on GPCR regulation led to paradigm shifts (inverse agonist, pharmacological chaperones, GPCR oligomerization, pluridimensionality of signaling), which coupled to his pioneering of bioluminescence resonance energy transfer (BRET) approaches, have direct impacts on drug discovery. He is the author of 262 scientific articles and of 36 patent applications and delivered more than 400 invited conferences.  His publications received more than 18,000 citations, leading to a Hirsh (h) index of 74 and his introduction on the 2014 Thomson Reuters’ list of the most cited scientists. His work was recognized by many awards, including his induction to the Academy of Sciences of the Royal Society of Canada in 2014 and the 2017 Julie Axelrod award from the American Society of Pharmacology and Experimental Therapeutics (ASPET). He trained 48 graduate students and 36 post-doctoral fellows, many of whom now hold professor and researcher positions around the world. He currently holds the Canada research Chair in Signal Transduction and Molecular Pharmacology and is the general director of the Institute of Research in Immunology and Cancer.  

Thursday, June 15

8:45 KEYNOTE PRESENTATION: Exploring the Pluridimensionality of G Protein-Coupled Receptor Signaling Efficacy; Potential Impacts for Drug Discovery - Click here for agenda 

Michel Bouvier, Ph.D., Professor/General Director, Biochemistry and Molecular Medicine/Institute for Research in Immunology and Cancer, Université de Montréal

It is now clear that G protein-coupled receptors can engage signaling pathways in a ligand-specific manner. Using BRET-based biosensors detecting the activity of multiple signaling pathways in living cells we characterized compounds based on multi-parametric analysis of their efficacy. Such pluridimensional description of compounds allows correlating signaling signatures to specific biological outcomes. Combined with structural analyses of the receptors, it also provides insights into the molecular basis of functional selectivity paving the way for the development of rationally designed biased ligands.

  

 1 What is the most important impact of GPCRs on drug discovery? GPCRs remain the single largest family of drug targets. They are proven tractable targets against which it is possible to find both small molecules and biologics that can bind with high selectivity and regulate function in predictable manner.  It is estimated that more than 30% of the current prescription drugs target GPCRs, yet only a small fraction of the GPCR family have been targeted to date. This means that, as a family, they still represent a large untapped potential for new therapeutics in many clinical indications. The fact that GPCR are involved in the regulation of almost all biological processes, makes them targets of choice not only for diseases that result from GPCR defects but also as targets that can attenuate or eliminate the functional manifestation of the primary defect.
 
 
2 Why is it important to understand Pluridimensionality of G Protein-Coupled Receptors? The fact that each GPCR can engage multiple signaling partners leading to multiple cellular responses led to the concept that different ligands can have distinct efficacies toward these different pathways. This is particularly important when considering that whereas some of the pathways may be important for therapeutic activity, others may be responsible for undesirable side effect and/or the development of tolerance. It follows that it is conceivable to design compounds that selectively modulate the therapeutically relevant pathways while sparing the detrimental ones. Such compounds known as biased or functionally selective ligands have already been identified and some of them have moved in clinical trials with the promise of generating better and safer drugs.

Conceptually, this means that drugs cannot anymore be considered as bi-dimensional switch regulators either activating or inhibiting a pathway. They need to be defined as a function of the ensemble of the signaling pathways that their target-receptor can engaged. Thus, a drug can be an agonist activating pathways A and C while being a neutral antagonist or even an inverse agonist inhibiting pathways B, D and E. We therefore need pluridimensional quantitative terms to exhaustively describe the signaling efficacy of a given receptor and to properly predict its therapeutic activity.    

 
   
 3 Where is the field headed in next 5 years and what’s revolutionizing GPCR research? 
1) I would say that three avenues will be extremely important for GPCR research in the next 5 years:
Our ability to use the structural information that is now being generated for many receptors to rationally design and/or optimize the next generation of drugs targeting these receptors. Getting high resolution structures for receptors in complex with ligands having different efficacies and with their different signaling partners should open the path for the conception of drugs with unmatched level of selectivity and efficacy.

2) Exploiting the fact that GPCRs are allosteric machines which activity can be regulated by binding at both orthosteric and allosteric sites with the potential of dialing-in the required level of activity. I would predict that in the next few years we will witness the clinical development of an ever-growing number of positive or negative allosteric modulators of GPCRs for many clinical indications.

3) Being able to harvest the therapeutic potential of GPCR pluridimensional signaling efficacy by identifying functionally selective drugs that regulated only the therapeutically relevant pathways.  A better understanding of the structural determinants of functional selectivity (i.e.: determining the receptor conformations responsible for the activation of specific signaling pathways) and of the links between specific signaling profiles and therapeutic activity on the one hand, and undesirable effects on the other hand, holds great promises for the development of better drugs.  

 

4. How is outsourcing and industry-academia collaborations shaping the future of drug discovery? This is most-likely one of the most significant change that has occurred in the drug discovery landscape in recent years. Finding ways of more efficiently transferring the knowledge from academia toward industry in a model of partnerships that benefits to both sides and accelerates the discovery of innovative drugs is essential for the future of the pharmaceutical Industry.  The level of complexity of the biological problems to be tackled and the sophistication of the approaches used require that the best specialists in the world be involved in the discovery process leading to major therapeutic breakthroughs. Yet, the know-how and efficiency of the industry in bringing projects forward from discovery to pre-clinical and clinical development is essential to deliver safe drugs to patients in a timely manner.  

Such collaborations cannot occur efficiently if left to random events. Specific structures need to be put in place to assure real bilateral exchanges between academic and industry scientists and to make sure that both risks and rewards associated with drug discovery are fairly shared.  An increasing number of centers have put in place such structures that allow academic drug discovery programs to be developed in partnership with industry. Different models have been put in place, and I think that we will see more of them. In my own institution, the institute for research in immunology and cancer (IRIC) of the Université de Montréal, we created a drug discovery unit (IRICoR) that assembles teams of medicinal chemists and biologists working side by side to translate discoveries into drug candidates.  This has led to mutually beneficial partnerships with pharmaceutical companies resulting in drug candidates now in clinical trials.