Exploiting Ligand-binding Domain Dimerization for Development of Novel Androgen Receptor Inhibitors

Abstract

Currently, all clinically used androgen receptor (AR) antagonists compounds which inhibit AR transactivation and dimerization of target the AR ligand-binding pocket and inhibit T and dihydrotesthe full-length AR as well as the isolated LBDs. Via biolayer tosterone (DHT) binding. Resistance to these inhibitors in prostate interferometry, reversible dose-dependent binding to the LBD was cancer frequently involves AR-dependent mechanisms resulting in confirmed. While DIM20 does not compete with 3H-DHT for a retained AR dependence of the tumor. More effective or alter-binding in the LBP, it limits the maximal activity of the AR native AR inhibitors are therefore required to limit progression in indicative of a noncompetitive binding to the LBD. DIM20 and these resistant stages. Here, we applied the structural information of DIM20.39 specifically inhibit proliferation of AR-positive prostate the ligand-binding domain (LBD) dimerization interface to screen cancer cell lines, with only marginal effects on AR-negative cell lines in silico for inhibitors. A completely new binding site, the Dimer-such as HEK 293 and PC3. Moreover, combination treatment of isation Inhibiting Molecules (DIM) pocket, was identified at the DIM compounds with enzalutamide results in synergistic antiproLBD dimerization interface. Selection of compounds that fit the liferative effects which underline the specific mechanism of action of DIM pocket via virtual screening identified the DIM20 family of the DIM compounds.