Small molecule inhibitors targeting the "achilles' heel" of androgen receptor activity

Abstract

Androgen ablation therapy remains the gold standard for the treatment of advanced prostate cancer, but unfortunately, it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer (CRPC). Mounting evidence supports the concept that development of CRPC is causally related to continued transactivation of androgen receptor (AR). All current therapies that target the AR are dependent on the presence of its C-terminal ligand-binding domain (LBD). However, it is the N-terminal domain (NTD) of the AR that is the "Achilles' heel" of AR activity, with AF-1 being essential for AR activity regardless of androgen. Recent efforts to develop drugs to the AR NTD have yielded EPI-001, a small molecule, sintokamide peptides, and decoys to the AR NTD with EPI-001, the best characterized and most promising for clinical development based upon specificity, low toxicity, and cytoreductive antitumor activity.

Figure 1. Therapeutic approaches to block the androgen receptor

A. EPI-001 interacts with the AR NTD to block CBP interaction and inhibit AR transcriptional activity. Inhibitors of the LBD include androgen ablation and antiandrogens (AA). CBP, CREB-binding protein; GnRH, Gonadotropin-releasing hormone (GnRH), also known as Luteinizing-hormone-releasing hormone (LHRH); DHT, dihydrotestosterone; NTD, N-terminal domain; DBD, DNA-binding domain; LBD, ligand-binding domain. B. Androgen dependent prostate cancer responds to androgen ablation and antiandrogens through the AR LBD. However, inhibition of the NTD with EPI-001 also inhibits androgen-dependent tumor growth. Castration resistant prostate cancer may involve: residual androgens that bind to the LBD; growth factor, cytokines, or kinase signal transduction pathways that target the NTD; constitutively active splice variants that lack the LBD that may be expressed solely or in mixed populations with full-length AR to form a heterodimer; and/or gain-of-function mutations. To date, EPI-001 inhibits all of these mechanisms with the possible exceptions of the heterodimer and the gain-of-function mutations which both have yet to be examined.