An Unexpected Mode Of Binding Defines BMS948 as A Full Retinoic Acid Receptor ß (RARß, NR1B2) Selective Agonist.

ABSTRACT

Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RARα, ß and γ. Multiple studies support that RARß possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RARß could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RARß-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RARß-selective ligand exhibiting a full transcriptional agonistic activity and activating RARß as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RARß ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RARα antagonist and an RARß full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180° of the amide linker, that usually confers RARα selectivity, accounts for the RARß selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RARß-selective antagonists.