A surface on the androgen receptor that allosterically regulates coactivator binding

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(41):16074-9. DOI: 10.1073/pnas.0708036104
Source: PubMed


Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.

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    • "Therefore, the AR still remains a key driver of castration-resistant prostate cancer. One of the promising strategies to combat resistance is to design compounds that target sites alternative to the androgen binding site in the AR ligand binding domain, such as the BF3 site, believed to function as a coregulatory site mediating coactivator recruitment (De Leon et al., 2011; Esté banez-Perpiñ a ´ et al., 2007). The BF3 regulatory site of the AR offers a direction for developing alternative AR-directed PCa therapeutics. "
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    ABSTRACT: There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen-induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Chemistry & biology 10/2014; 21(11):1476-1485. DOI:10.1016/j.chembiol.2014.09.012 · 6.65 Impact Factor
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    • "Studies on other members of the NR superfamily, such as estrogen receptors (ER) and progesterone receptor (PR), also revealed that the AF2 region on LBD is the binding site of some antagonists [20-23]. Besides, another novel binding site, binding function 3 (BF3), on the LBD have been identified by a recent virtual screening study combined with biochemical assays and X-ray crystallography [24,25] (see Figure 2). "
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    • "together with structural information from LBD crystal structures of other NRs (e.g. Androgen Receptor LBD, PDB 1T5Z [29]; COUP-TFII, PDB 3CJW [30]–[31]). "
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