Fenoprofen-An Old Drug Rediscovered as a Biased Allosteric Enhancer for Melanocortin Receptors

It is time-consuming and costly to bring new drugs to market, making it necessary and urgent to exploit existing drugs for new uses. Recently, fenoprofen was demonstrated as an allosteric modulator at melanocortin receptors (MCRs), although the exact mode of action has not been clarified. MCRs regulate multiple functions, including pigmentation, adrenal steroidogenesis, inflammation, energy homeostasis, and exocrine gland secretion. In this study, we showed that fenoprofen failed to displace the orthosteric agonist Nle⁴-d-Phe⁷-α-melanocyte stimulating hormone from binding to MC3-5R while possessing positive allosteric modulator activities at these receptors. In addition, fenoprofen induced biased signaling at MC3-5R, as it selectively activated ERK1/2 cascade but not the canonical cAMP signaling. Notably, fenoprofen stimulated biased signaling at MC3-5R, but not at MC1R, hence acting selectively among this highly conserved family of receptors. Moreover, PAM activity and biased signaling induced by fenoprofen were observed not only at wild-type but also at naturally occurring mutant MC3Rs, suggesting that this biased allosteric enhancer action might constitute as novel therapeutic opportunity for obese patients harboring these mutations. Our study might guide novel therapeutic applications for repurposing current drugs or designing new drugs combining allosteric and biased properties.