Abstract

Natural products and their derivatives have long served as a prolific reservoir for drug discovery. All-trans retinoic acid (ATRA) regulates lipid metabolism and shows anti-atherosclerotic potential, but its application is limited by poor drug-like properties and retinoid-related toxicity. Here, an allene-based Chem-Stamp technology has empowered the efficient construction of a diverse non-natural ATRA library by fine-tuning the number of isoprene units, the side chain, and the terminal group, leading to the identification of G301-WSS-2003 as a novel ATRA-based LDLR up-regulator. In vivo, G301-WSS-2003 , with favorable exposure and bioavailability (e.g., t 1/2 > 5 h, F > 30%), reduced serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) by 27%, 36%, and 26%, respectively, and significantly attenuated atherosclerotic lesion formation with no liver function abnormalities. These results highlight that Chem-Stamp is a powerful technology platform in the discovery, which results in identifying G301-WSS-2003 for further development as a promising candidate for the treatment of atherosclerosis.