Small molecule inhibitors as probes for estrogen and androgen receptor action

Abstract

Because activated estrogen (ER) and androgen (AR) receptors stimulate cell proliferation in breast and prostate cancer, inhibiting their actions represents a major therapeutic goal. Most efforts to modulate ER and AR activity have focused on inhibiting the synthesis of estrogens or androgens or on the identification of small molecules that act by competing with agonist hormones for binding in the ligand-binding pocket of the receptor. An alternative approach is to implement screens for small molecule inhibitors that target other sites in the pathway of steroid receptor action. Many of these second-site inhibitors directly target ER or AR; others have still unknown sites of action. Small molecule inhibitors that target second sites represent new leads with clinical potential; they serve as novel modulators of receptor action; and they can reveal new and as yet unidentified interactions and pathways that modulate ER and AR action.

FIGURE 1.

Schematic representation of some sites targeted by small molecules used to selectively block ERα action and breast cancer cell growth. Current small molecule modulators largely target estrogen synthesis and competition with E₂ for binding in the ligand-binding pocket of ERα. Actions of ERα targeted by the small molecules discussed here included coactivator binding, DNA binding, and receptor degradation. SERMS, selective ER modulators; TAM, tamoxifen.

FIGURE 2.

Structure of the AR LBD with T₃ bound to AR BF-3. The ribbon diagram shows the AR LBD liganded with dihydrotestosterone (brown) and T₃ (purple) bound at BF-3. The dot-filling model illustrates the residues in the AF-2 core (prepared using Jmol from Protein Data Bank code 2PIV).

FIGURE 3.

Structurally similar TPBM and TPSF have very different modes of action. A, shown are the structures of the ERα inhibitors TPBM and TPSF. B, in contrast to TPBM, TPSF does not inhibit binding of E₂-ER to a fluorescein-labeled cERE. C, Western blot analysis shows that TPSF elicits a concentration-dependent decline in ERα levels. In contrast, TPBM has no effect on effect on the level of ERα (redrawn from Ref. 47).