LB1570 Structure-based Design of Trifarotene, a Potent and Selective RAR Agonist for the Treatment of Acne

Retinoids have a dominant role in topical acne therapy and to date, only RARβ and RARγ dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARγ –selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-Ray structure of known γ–selective CD437, revealed an unprecedented and isotype specific pocket in the RARγ ligand binding domain and enabled the optimization of a novel triaryl series of agonists which ultimately led to the discovery of Trifarotene.