Signaling bias in drug discovery

ABSTRACT

Introduction: The availability of different functional pharmacological assays has revealed that agonists for receptors that are pleiotropically coupled to multiple signaling pathways in the cell can emphasize signals to some pathways over others, i.e. can be biased toward certain signals. This, in turn, opens the possibility that molecules can be made to emphasize favorable signals, de-emphasize harmful signals or selectively block the ability of the natural agonist to produce unfavorable signals.

Areas covered: This paper discusses the mechanism of biased signaling, the possible therapeutic implications of this effect, methods to quantify and measure bias and the current literature describing the translation of biased measure in vitro to in vivo systems. In addition, the challenges of exploiting this mechanism for therapy are outlined.

Expert opinion: While this mechanism is well established and ubiquitous in pharmacology and easily measured in vitro, there are theoretical and practical hurdles to overcome to the fruitful utilization of signaling bias in therapeutic systems. There will be failures in the translation of biased molecules in vivo because of these challenges but hopefully also success and these latter translations hopefully will provide guidance in exploiting this effect further for therapy.

KEYWORDS:

• ((Allosteric) OR allosterisms) OR allostery
• receptors
• biased signaling
• drug discovery

Article highlights

• Receptors pleiotropically are coupled to multiple signaling pathways in accordance with the needs of the cell; some agonists extend this biased signaling by stabilizing unique receptor active states to emphasize some signals at the expense of others

• Biased signaling can be quantified by canceling effects of assay sensitivity by comparing responses to test agonists to a common reference agonist and utilizing ΔLog(τ/K_A) values for agonism

• Comparing responses with varying kinetics can affect the magnitude of differences in signaling bias; this effect must be considered in experimental measuring of the effect.

• A major challenge in the exploitation of biased signaling for therapy is prediction of biased effects to in vivo systems

• Biased activation of signaling pathways in cells can be modified by different types of host cells to change bias measured in test systems to yield new and different cell-specific profiles of agonism.

• Allosteric modulators can induce signaling bias in natural systems; this effect should be considered in measuring the effect of allosteric ligands.

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Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript has not been funded.