Scientists discover new drug candidate that rewires how cells respond to lactate
Researchers identified a compound called AZ7136 that activates HCAR1, a receptor tied to fat burning and blood sugar control. The finding opens a new path for obesity and diabetes treatments, potentially worth billions in the pharmaceutical market if it moves toward clinical use.
Originaltitel: Profiling of HCAR1 signalling reveals Gαi/o and Gαs activation without β-arrestin recruitment and the discovery of an allosteric agonist
Background and Purpose Lactate, historically viewed as a metabolic by-product, has emerged as a signalling molecule via the G protein-coupled receptor Hydroxycarboxylic Acid Receptor 1 (HCAR1). The receptor is primarily expressed in adipocytes but also found in various other tissues. HCAR1 activation has been shown to regulate lipolysis and improve insulin sensitivity, positioning it as a promising therapeutic target for metabolic disorders such as obesity and type 2 diabetes. Despite its potential, its role in cancer progression and the limited availability of characterized ligands necessitate further investigation into its signalling mechanisms. This study aimed to broaden the pharmacological understanding of HCAR1 by investigating previously uncharacterized ligands and profiling their signalling properties.Experimental Approach We employed enhanced bystander bioluminescence resonance energy transfer (ebBRET) assays to investigate G protein activation and beta-arrestin recruitment following ligand stimulation of HCAR1. A panel of compounds was screened to identify more potent agonists and modulators of HCAR1 signalling.Key Results We identified AZ7136 as a relatively potent HCAR1 agonist, AZ2114 as a partial agonist, and GPR81 agonist 1 as an ago-positive allosteric modulator. HCAR1 preferentially activated G alpha i/o and G alpha s pathways without recruiting beta-arrestins, revealing a distinct signalling profile.Conclusion and Implications These findings expand our understanding of HCAR1 signalling and introduce new molecular tools for probing its physiological and pathological roles. The characterized ligands may support future therapeutic strategies targeting HCAR1 in metabolic disorders while informing approaches to mitigate potential oncogenic effects.