Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide) and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR–CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm, bound to heat shock proteins. Thus, we have identified third-generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.
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This work was supported by grants from the CDMRP (Synergistic Idea Development Award W81XWH-10-1-0179 to D.P.M. and J.A.K.), the NIH (PHS5R01DK015556 to J.A.K.), and the DOD (W81XWH-13-1-0196 to J.D.N.). J.A.P. was supported by an NIH Training grant (T32ES007326). A.A.P. was supported by NIH NRSA (1 F30 DK083899). We would like to thank J.R. Gunther, K.E. Carlson, and T.A. Martin for their early contributions to the project. We are thankful to P. Fan for performing the LC/MS/MS assays within the PK/PD Core Laboratory. I.S. is grateful for the support of the Pharmaceutical Research Shared resource–PK/PD Core laboratory by NIH/NCI Core Grant, 5-P30-CA14236-29.
A patent covering this work has been published (Publication No. WO 2015/048246).
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Pollock, J., Wardell, S., Parent, A. et al. Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer. Nat Chem Biol 12, 795–801 (2016). https://doi.org/10.1038/nchembio.2131