A New Strategy for Selective Targeting of Progesterone Receptor With Passive Antagonists

摘要: Currently available progesterone (P4) receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use. Recent x-ray crystallographic studies have identified key contacts involved the binding of agonists antagonists with PR opening way for a new rational strategy inactivating PR. We report here synthesis characterization novel class (APRn) designed from studies. The lead molecule, homosteroid APR19, displays vivo endometrial anti-P4 activity. APR19 inhibits P4-induced recruitment transactivation synthetic endogenous gene promoters. Importantly, it exhibits high selectivity respect other steroid hormone receptors is devoid any activity on target transcription. Two-hybrid immunostaining experiments reveal that APR19-bound unable interact either coactivators 1 2 (SRC1 SCR2) or nuclear corepressor (NcoR) silencing mediator retinoid acid thyroid (SMRT), contrast RU486-PR complexes. also agonist-induced phosphorylation serine 294 regulating transcriptional turnover kinetics. In silico docking based crystal structure ligand-binding domain show that, P4, does not establish stabilizing hydrogen bonds cavity, resulting an unstable ligand-receptor complex. Altogether, these properties highly distinguish RU486 likely its derivatives, suggesting belongs pure antiprogestins inactivate by passive mechanism. These specific open perspectives long-term hormonal therapy.