揭示一种作为新型RAR激动剂的天然海洋产物及其用途

Retinoids display antitumor activity on various cancer cells and thereby have been used as important therapeutic agents. However, adverse side effects and retinoic acid (RA) resistance limit further development and clinical application of retinoid-based therapeutic agents. We report here the identification of a natural marine product that activates retinoic acid receptors (RARs) with a chemical structure distinct from retinoids by high-throughput compound library screening. Luffariellolide, was uncovered as a novel RAR agonist by inducing coactivator binding to these receptors in vitro, further inhibiting cell growth and regulating RAR target genes in various cancer cells. Structural and molecular studies unraveled a unique binding mode of this natural ligand to RARs with an unexpected covalent modification on the RAR receptor. Functional characterization further revealed that luffariellolide displays chemotherapeutic potentials for overcoming RA resistance in colon cancer cells, suggesting that luffariellolide may represent a unique template for designing novel non-retinoid compounds with advantages over current retinoic acid drugs.