Androgen Receptor Inhibitors

The development of anti-androgens with a new mechanism of action for treatment of castration resistant prostate cancer


  • Targets the androgen receptor (AR) at the BF-3 pocket rather than the hormone binding site (HBS). Works in virtually every known AR-HBS mutation associated with enzalutamide resistance (unpublished) and should also be effective in AR-HBS mutation resistance associated with ARN-509 or ODM-201
  • Excellent anti-AR activity, PSA reduction and anti-proliferative effect against PCa cell lines, including enzalutamide resistant cell lines (MR49F)
  • 500 compound med chem program over 6 years, 250 if which were custom compounds. The lead compound has IC50 of 70-90 nM, T1/2 at ~4hrs (human microsomal)

Technology Details


Prostate cancer is the second leading cause of male cancer-related death in Western countries.  Numerous studies have shown that the androgen receptor (AR) is central not only to the development of prostate cancer, but also the progression of the disease to the castration resistance state.  Thus, effective inhibition of human AR remains one of the most effective therapeutic approaches to the treatment of advanced, metastatic prostate cancer.

The AR possesses a modular organization characteristic of all nuclear receptors.  It is comprised of an N-terminal domain, a central DNA binding domain, a short hinge region, and C-terminal domain that contains a hormone ligand binding pocket and the Activation Function-2 (AF2) site. Recent studies have identified a novel site on the AR called Binding Function 3 (BF3) that is involved into AR transcriptional activity. It has been proposed that a small molecule bound to the BF3 site could prevent AR interactions with co-activators.  Importantly, the BF3 site is located near, but distinct from, the ligand-binding site that is normally targeted by other conventional anti-androgen drugs.

The activation of AR follows a well characterized pathway: in the cytoplasm, the receptor is associated with chaperone proteins that maintain agonist binding conformation of the AR.  Upon binding of an androgen, the AR undergoes a series of conformational changes, disassociation from chaperones, dimerization and translocates into the nucleus where it further interacts with co-activator proteins at the AF2 site to form a functional transcriptional complex. Notably, the current anti-androgens such as bicalutamide, flutamide, nilutamide and enzalutamide all target this particular process.  However, instead of affecting the AR-cofactor interaction directly, these anti-androgens act indirectly by binding to the AR ligand binding site.  Thus, by preventing androgens from binding they also prevent conformational changes of the receptor that are necessary for co-activator interactions. While treatment with these AR inhibitors can initially suppress the prostate cancer growth, long term hormone therapy becomes progressively less effective. Factors that make the AR less sensitive to conventional anti-androgens include resistance mutations at the ligand binding site that can even lead AR antagonists to act as agonists, further contributing to cancer progression.

Our Solution

The BF3 site is an attractive target for direct inhibition of the AR co-activation. Using a variety of in silico computational drug discovery methods, ≥ 500 BF3 inhibitors were tested for anti-AR activity. Our BF3 inhibitors demonstrate excellent anti-AR activity, PSA reduction and anti-proliferative effect against PCa cell lines, is effective on anti-androgen resistant mutants (including ARN509 and Enzalutamide resistant), and can reduce the growth of enzalutamide-resistant tumors in a xenograft models. We believe that BF3 inhibitors have the potential to provide a further line of treatment after failure of second generation anti-androgens.

Technology Details 

In silico computational drug discovery methods were used to conduct a virtual screen of ~4 million purchasable lead-like compounds from the ZINC database. Subsequent systematic hit-to-lead optimization resulted in the identification of the compounds that stably bind the BF3 pocket, possesses an anti-proliferative effect against PCa cell lines, are effective against clinically relevant AR Mutations (including anti-androgen resistant mutations), and reduces tumor volume in enzalutamide-resistant LNCaP (T877A) and MR49F (F876L) xenograft models. Our current lead compound (VPC-13789) possesses an IC50 of 70-90nM (transcription assays and cell viability) and a T ½ of ~4 hours (human microsomal). Data displayed below was obtained using VPC-13566, from which the current lead compound was derived.  

Figure 1 – VPC-13566 reduces growth of prostate cancer tumors. 6-8 week-old nude mice (n=27) were subcutaneously inoculated with LNCaP cells and divided into 3 groups (control, enzalutamide-treated, and 13566-treated).  Mice were treated when serum PSA levels reached more than 25ng/ml, and experimental groups were administered either enzalutamide or 13566 (i.p.) twice daily for 4 weeks.