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

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

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©2022 American Association for Cancer Research.