Clinical translatability

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GPCR signaling profiles translatable to clinical outcomes

GPR109a profiling: case study

GPR109a is a receptor that’s been shown to display numerous beneficial effects once engaged, including anti-lipolytic, anti-inflammatory and anti-atherogenic effects. The receptor can couple not only to G proteins but also β Arrestins. However, for a considerable proportion of individuals, use of Niacin leads to adverse effects (cutaneous inflammation event referred to as “Flushing“).

It was shown that GPR109a’s beneficial effects were mediated by the G protein signaling arm of the receptor signaling while the side effects were mediated by the β Arrestin arm. Based on these findings, tremendous efforts by pharma companies are aimed at developing compounds that would engage the G protein signaling arm of the receptor and avoid activation of the β Arrestin signaling cascade.

To prove this correlation between ligand’s signaling signature and clinical outcome, we present below the comparison of different ligands. The compound developed by Merck, MK-1903 is known to evoke minimal flushing side effect, this compound indeed did not recruit the β Arrestin arm (figure below).

Hence, ligand profiling early during the drug discovery process can be valuable in identifying / designing the right therapeutic (small molecules and biologics), with potentially optimal therapeutic effects, minimizing the risk of attrition during clinical trials.

Clinical effect signaling profile
Signaling profiles correlated to in vivo effects