Biased agonism in drug discovery: is it too soon to choose a path?

Michel, Martin C.; Charlton, Steven J.

Abstract

A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more targeted modulation of cell function and treatment of disease. Dedicated development of biased agonists has led to promising drug candidates in clinical development, such as the G protein-biased µ opioid receptor agonist oliceridine. However, leveraging the theoretical potential of biased agonism for drug discovery faces several challenges. Some of these challenges are technical, such as techniques for quantitative analysis of bias and development of suitable screening assays; others are more fundamental, such as the need to robustly identify in a very early phase which cell type harbors the cellular target of the drug candidate, which signaling pathway leads to the desired therapeutic effect, and how these pathways may be modulated in the disease to be treated. We conclude that biased agonism has potential mainly in the treatment of conditions with a well-understood pathophysiology; in contrast, it may increase effort and commercial risk under circumstances where the pathophysiology has been less well defined, as is the case with many highly innovative treatments.

Citation

Michel, M. C., & Charlton, S. J. (2018). Biased agonism in drug discovery: is it too soon to choose a path?. Molecular Pharmacology, 93(4), https://doi.org/10.1124/mol.117.110890

• Journal Article Type: Article
• Acceptance Date: Jan 1, 2018
• Online Publication Date: Mar 20, 2018
• Publication Date: Apr 1, 2018
• Deposit Date: Mar 22, 2018
• Publicly Available Date: Mar 21, 2019
• Journal: Molecular Pharmacology
• Print ISSN: 0026-895X
• Electronic ISSN: 0026-895X
• Publisher: American Society for Pharmacology and Experimental Therapeutics
• Peer Reviewed: Peer Reviewed
• Volume: 93
• Issue: 4
• DOI: https://doi.org/10.1124/mol.117.110890
• Public URL: https://nottingham-repository.worktribe.com/output/922858
• Publisher URL: https://doi.org/10.1124/mol.117.110890