The Effective Application of Biased Signaling to New Drug Discovery

Abstract

The ability of agonists to selectively activate some but not all signaling pathways linked to pleiotropically signaling receptors has opened the possibility of obtaining molecules that emphasize beneficial signals, de-emphasize harmful signals, and concomitantly deemphasize harmful signals while blocking the harmful signals produced by endogenous agonists. The detection and quantification of biased effects is straightforward, but two important factors should be considered in the evaluation of biased effects in drug discovery. The first is that efficacy, and not bias, determines whether a given agonist signal will be observed; bias only dictates the relative concentrations at which agonist signals will appear when they do appear. Therefore, a Cartesian coordinate system plotting relative efficacy (on a scale of Log relative Intrinsic Activities) as the ordinates and Log(bias) as the abscissae is proposed as a useful tool in evaluating possible biased molecules for progression in discovery programs. Second, it should be considered that the current scales quantifying bias limit this property to the allosteric vector (ligand/receptor/coupling protein complex) and that whole-cell processing of this signal can completely change measured bias from in vitro predictions.

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

“…Ligand bias, which is the ability of a compound to selectively promote transduction of information from a receptor via a subset of the panoply of signaling pathways the receptor can engage with, compared with the effects produced at the same pathways by a reference compound, is now well established and widely discussed (38–40). Initially, studies on ligand bias focused primarily on proof-of-concept and were frequently limited to experiments performed using receptors expressed in heterologous cell systems.…”

Biased Receptor Signaling in Drug Discovery

“…This gives the illusion of "perfect bias" in that no response in one of the pathways is observed, further implying no interaction of the receptor with that signaling protein. However, experiments in which the "perfectly biased" ligand is used as an antagonist indicate that an interaction between the receptor and b-arrestin actually is taking place but no overt agonism can be displayed (Kenakin, 2015b;Stahl et al, 2015). A classic example of this is shown with the angiotensin biased ligand TRV120027, where the lack of G q protein response is further shown to be a competitive antagonism of angiotensin G q -mediated responses through Schild analysis (Violin et al, 2010).…”

Biased agonism: An emerging paradigm in GPCR drug discovery

“…49,73,74 However, a framework for quantitatively ranking the degree of bias of these compounds has only just begun to emerge. 61,75 As these quantitative, mechanistic methods become more accepted and elaborative there is certain to be a broader interest in both the discovery and interpretation of the molecular and physiological implications of extremely biased ligands. Again, it is important to emphasize that bias is context dependent and bias observed in one condition (i.e., cell-based signaling assay) may not translate to the receptor expressed in an endogenous setting (i.e., synapse).…”