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  • Herein in consider of the high similarity between

    2021-10-11

    Herein, in consider of the high similarity between GR HBP site and AR HBP site, we applied rational drug design strategy to develop AR/GR antagonists based on the chemical structures of antiandrogens and crystal structure of GR. The following bioassay identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream LY 2389575 hydrochloride of GR and AR signaling (PSA for AR, KLF9 for GR). Specially, Z19 did not inhibit the protein and mRNA levels of AR and GR themselves, which indicated that Z19 inhibited the AR/GR signaling through directly targeting AR/GR rather than causing the degradation of AR/GR. Molecular docking and ForteBio binding assay further suggested that Z19 might bind to the HBP site of AR and GR. Thus, our work demonstrates rational drug design is an efficient strategy in development of antiandrogen. What is more, the strategy used herein belong to the combination of ligand and target based polypharmacology drugs design [22]. Among 99 hits, ten compounds showed dual AR/GR activity, which indicated that structural based drug design like molecular docking combing with the ligand based pharmacophore screening is an efficient strategy in lead compounds discovery for dual-targets inhibitor. Such strategies have also been applied to the discovery of other dual inhibitors like AChE and BuChE dual inhibitor [28] or hLTA4H and hLTC4S dual inhibitor [29]. “Multiple target drug” concept has been becoming more and more attractive in drug discovery. Up to now, several multiple target antiandrogens have been reported. Abiraterone, which was approved in 2013, were found directly acting on CYP17, 3β-HSD, and AR, and its multiple targets interaction properties were important for the anti-PCa potency [30]. Interestingly, D4A, a metabolite of abiraterone, has similar multiple targets interaction profile but with higher affinity and better potency than abiraterone [31]. Galeterone, another antiandrogen under development, possesses a unique dual mechanism of action, acting as both an androgen receptor antagonist and a CYP17A1 inhibitor [32]. For AR and GR dual antagonist, the pyrrole imidazole polyamide ARE-1 was found binding to AR response element (ARE) DNA, and prevented the transcriptional activity of AR and GR. Otherwise, our group and other research group indicated that triptophenolide from tripterygium wilfordii was a dual inhibitor for AR and GR [33]. However, the mechanism of anti-GR activity for triptophenolide remains unclear. Up to now, Z19 is the first dual AR/GR inhibitor that is supposed to bind to the HBP sites of GR and AR, and thus providing a lead compound for the development of novel treatment agents of prostate cancer.
    Conclusions
    Methods
    Acknowledgments We thank Dr. Jianhui Wu (Mcgill University), and Dr. Hiroyuki Seimilya (Cancer Chemotherapy Center, Japan) for providing AR expressing plasmids. This work was in part supported by the Nature Science Foundation of China (81672559, 81311120299, 81271844), CAMS Innovation Fund for Medical Sciences (CAMS-I2M-1-012 ZJM), and National key research and development program (2016YFA0201500).
    Introduction The chemicals to which an organism is exposed and which are extrinsic to the metabolism of that organism are referred to as xenobiotics (Croom, 2012). Xenobiotics that humans are exposed to include a vast range of possibilities; occupational chemicals, pesticides, illicit, over the counter and prescription drugs, environmental contaminants, deployment-related chemicals, exogenous chemicals generated by other organisms, and the list continues (Croom, 2012). Xenobiotics are eliminated via the kidneys or gastrointestinal tract having undergone no to extensive metabolism. Xenobiotic metabolizing enzymes are capable of metabolizing several different classes of xenobiotics so that the same enzyme isoform that successfully metabolizes pharmaceuticals can be just as effective in the metabolism of pesticides (e.g. the Cytochrome P450 enzyme sub-type CYP3A4). Without the ability for metabolic breakdown, xenobiotics would accumulate in the human body culminating in potentially lethal toxicity (Croom, 2012).