Discovery of Thiadiazoleamide Derivatives as Potent, Selective, and Orally Available Antagonists Disrupting Androgen Receptor Homodimer.

Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist was identified. showed strong efficacy against PCa but had poor pharmacokinetic properties .

Small-Molecule Inhibition of Androgen Receptor Dimerization as a Strategy against Prostate Cancer.

The clinically used androgen receptor (AR) antagonists for the treatment of prostate cancer (PCa) are all targeting the AR ligand binding pocket (LBP), resulting in various drug-resistant problems. Therefore, a new strategy to combat PCa is urgently needed. Enlightened by the gain-of-function mutations of androgen insensitivity syndrome, we discovered for the first time small-molecule antagonists toward a prospective pocket on the AR dimer interface named the dimer interface pocket (DIP) via molecular dynamics (MD) simulation, structure-based virtual screening, structure-activity relationship exploration, and bioassays.

Design, synthesis and biological evaluation of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues as multiple functional agents with the potential for the treatment of Alzheimer's disease.

A novel series of 2-styryl-5-hydroxy-4-pyrone derivatives and analogues were designed and synthesized as H receptor antagonism based multitarget-directed ligands (MTDLs) for AD therapy using pharmacophore-combine strategy. The 2-styryl-5-hydroxy-4-pyrone pharmacophore with metal ion chelation, antioxidation, and Aβ aggregation inhibition activities was employed as the "eastern part", and a typical phenoxyalkylamine moiety was used as "central ring + western part" of the H receptor antagonist. The biological evaluation revealed that the majority of the target compounds demonstrated desirable multiple functions.