Dr Yan from Pfizer to present at the next Keystone symposia on April 6th, 2022
Pfizer will be participate in the next Keytsone meeting workshop: GPCRs: An Odyssey from Structure, Signaling and Regulation to Therapeutics
Dr Dong Yan will present Pfizer’s researches on the “Exploration of Novel G-protein Coupled Receptor Targets through Large Scale Multi-parametric Characterization of Human Missense Variants“.
This presentation will be based on the collaboration between Domain Therapeutics and Pfizer, using the bioSensAll® platform technology.
Exploration of novel G-Protein Coupled Receptor (GPCR) targets through large scale multi-parametric characterization of human missense variants.
Dong Yan1, Melissa Miller1, Shunjie Guan2, Hye In Kim1, Meriem Semache3, Claire Normand3, Jenny Lau3, Sandra Morissette3, Arturo Mancini3, Stephan Schann3, Xavier Leroy3, Laurent Sabbagh3, Craig Hyde2, Eric Fauman1, Bei Zhang1, and Jean-Philippe Fortin1.
1 Internal Medicine Research Unit, 2 Non-clinical Statistics, Early Clinical Development, Worldwide Research Development and Medical, Pfizer, 3 Domain Therapeutics.
Abstract:
G protein-coupled receptors (GPCRs) represent a successful drug target class with large untapped potential. For many established targets, the molecular characterization of disease-causing or disease-preventing missense variants has provided valuable human biology insights and supports the mode of action of therapeutics acting at those receptors. To exploit the potential of naturally occurring GPCR mutations emerging from large scale exome and genome sequencing efforts, we present a novel target validation approach: Human Genetics Structure Activity Relationship (HG-SAR). This method leverages the power of human genetics by linking the molecular, cellular, and clinical consequences of rare missense variations to accelerate the discovery of disease relevant pathways. As a proof-of-concept, we report the multiparametric profiling of over 200 beta-1 adrenergic receptor (ADRB1) variants, several of them showing unique pharmacological features. Follow-up HG-SAR analyses showed that reduced variant signaling efficacy on the G15 and β-arrestin pathways is associated with a corresponding reduction in blood pressure. Importantly, such HG-SAR findings closely mirror the clinical efficacy of β adrenoceptor selective blockers used to treat hypertension in humans. A similar strategy was applied to variants in the melanocortin-4 receptor (MC4R) gene, where the HG-SAR analysis demonstrates a linear relationship between altered MC4R signaling and changes in body weight. Supporting human translation of this mechanism, HG-SAR analyses show that for each 10% decrease in MC4R G15 signaling, body weight increases by 0.76 kg. We believe this same approach can be applied to other GPCRs to help facilitate validation of novel GPCR-based therapeutic concepts and improve translation from bench to clinic.