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    • br Acknowledgments This work was funded by NIH Grant

    2021-12-01


    Acknowledgments This work was funded by NIH Grant 2R01 MH066958 (JGT) and NSF CAREER award IOS- 1053716 (NV). We thank Dr. Greti Aguilera for the generous gift of the GRE-Luciferase construct and Dr. Louis Muglia for the generous gift of the GR-GFP construct.
    Introduction Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in the western countries [1,2]. A significant fraction of advanced stage prostate cancer patients treated with androgen deprivation therapy (ADT) experience relapse, and finally progress to lethal metastatic castration-resistant prostate cancer (mCRPC) which is stimulated by the intratumoral synthesis of testosterone and/or 5α-dihydrotestosterone (DHT) and the activation of the androgen receptor (AR) [[3], [4], [5], [6]]. Through binding to the androgen receptor with high affinity and blocking androgen responsive signaling, the second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC [7,8]. However, inherent or acquired resistance in ENZa therapy remains a clinical challenge during mCRPC treatment [[9], [10], [11]]. Accumulating data suggest that potent AR inhibition with ENZa can increase glucocorticoids receptor (GR) expression, which regulates about 50% of AR-responsive genes re-expression, thus promoting PCa tumor proliferation despite the blockage of AR signaling [12]. GR agonists, such as dexamethasone (Dex), are sufficient to cause ENZa resistance, whereas a GR antagonist could restore sensitivity of ENZa [13,14]. Li et al. and Shah et al. found that GR pathway blockage could restore sensitivity of ENZa resistance Lomustine to ENZa therapy both in vitro and in vivo [15,16]. Increased GR expression also has been observed when another AR pathway inhibitor (Abiraterone) is treated, which indicates the GR signaling activation represents a general mechanism of resistance to antiandrogens [14]. Therefore, blocking of both AR and GR signaling pathway may be an efficient strategy to overcome the drug resistance in antiandrogen therapy of mCRPC. Multiple target drug (a single drug acting on multiple targets) strategy is recognized as a new valuable opportunity for drug discovery and development [17]. Efforts have been made by blocking GR and AR signal pathway to escape antiandrogen resistance especially ENZa resistance in PCa. In a recent study, a pyrrole-imidazole polyamide ARE-1 showed both AR and GR transcription blockage and inhibited ENZa-resistant mCRPC xenografts progression [18,19]. Thus, simultaneously blocking AR and GR by multi-target drug [20,21] may overcome ENZa resistance mCRPC caused by GR overexpression. Rational drug design, which combines the computational tools and structural information, has become the most promising and attractive strategy in multiple target drug discovery [22]. Importantly, GR and AR both belong to 3-ketosteroid receptors group of nuclear receptor superfamily and bear quite similar sequence for their ligand binding domain, and the hormone binding pockets (HBP) of them are quite similar both in structure and sequence. Therefore, it is quite plausible to develop the GR/AR dual antagonist through rational drug design. Herein, according to the chemical structures of antiandrogens and crystal structure of GR, we set up to develop GR/AR dual antagonist by combining virtual screening and biological evaluation, and identified Z19 as a GR/AR dual antagonist. Z19 provides a potential agent in therapy of the GR overexpression mCRPC. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate cancer.
    Results
    Discussion Drug resistance of current clinically used antiandrogens is severe problem during therapy of mCRPC. The GR signaling activation is a general mechanism of resistance to antiandrogens. Recently, the clinical trial combining ENZa and Mif is ongoing (NCT02012296, Phase I/II), and the detail data is not released yet. Compared to multiple molecules in combination, a single molecule with dual activity may have a more predictable pharmacokinetic profile and avoid the risks of drug-drug interactions associated with combination therapies. Therefore, we herein toke the multiple target drug strategy to develop the dual AR/GR antagonist to conquer GR overexpression induced drug resistance of mCRPC. Apart from GR activation, up to now, there are multiple other mechanisms involved in drug resistance of antiandrogen in mCRPC. The acquired AR mutations like T877A, W741L and F876L would switch the clinically used antiandrogens from antagonist to agonist [25]. AR splice variants missing LBD domain like AR-V7, AR-V567 are key mediators of persistent AR signaling and resistance to AR-directed therapies [26]. Another important resistance mechanism is the neuroendocrine differentiation in PCa, which is resistant to antiandrogen therapy and usually associated with nodal or/and distant metastases [27]. Thus, there are still big challenges remaining in treatment of PCa.