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    • Furthermore new strategies to achieve

    2024-03-15

    Furthermore, new strategies to achieve a total androgen deprivation namely by blocking either androgen biosynthesis as well as AR are being considered and should be a relevant topic in the near future. A successful example of this approach is galeterone (159), which not only inhibits the CYP17 enzyme but also modulates AR activity and is now in Phase I/II clinical trials for CRPC.
    Introduction Multiple human diseases, such as prostate and breast cancers, benign prostate hyperplasia, endometriosis, and polycystic ovarian syndrome, are driven by the biological effects of steroid hormones. For example, progression of prostate cancer, one of the leading causes of cancer death in men worldwide [1], was shown more than 50 years ago to be dependent on circulating levels of testosterone [2]. Since then, surgical castration (hormone ablation therapy) has constituted a major medical treatment for recurrent and locally advanced or metastatic prostate cancers, for which radical prostatectomy is no longer an option. As an alternative to surgical castration, medical castration (i.e., treatment with gonadotropin-releasing hormone [GnRH] agonists such as leuprorelin) has been shown to suppress gonadal androgen production with similar efficacy and is now first-line therapy for this disease. Unfortunately, while most prostate cancers initially respond to androgen ablation therapy, they almost uniformly acquire resistance to this approach within 2–3 years, associated with a rise in prostate specific androgen (PSA). Of interest, disease progression following hormone ablation therapy is still driven by circulating androgens despite castration levels of testosterone (<50ng/dL). Prostate cancer under these conditions is called castration-resistant (CRPC) and the prognosis is poor [3], [4]. Until recently, docetaxel was the only chemotherapeutic ahr inhibitor shown to have survival benefit in patients with CRPC [5] despite its moderate efficacy and frequent adverse effects. Clearly new treatment options for CRPC are urgently needed. Studies have established the importance of androgen receptor (AR) signaling in all stages of prostate cancer, including CRPC. In CRPC, several mechanisms such as AR activation by non-gonadal (adrenal and/or intratumoral) androgens, AR hypersensitivity through over-expression of AR, and associated proteins [6], [7], [8], [9], or promiscuous/constitutive activation of mutant AR [10], [11], [12], [13], [14], [15], [16], [17], [18], [19] have been proposed to explain ongoing AR activation in the face of castrate androgen levels. Regarding the role for extragonadal androgen synthesis, it is interesting to note that expression levels of the enzymes responsible for converting adrenal androgens to testosterone and dihydrotestosterone (DHT) are up-regulated in CRPC tissues [20]. Biochemically, both testicular and adrenal androgens are synthesized from cholesterol through a multi-step process in which the 17,20-lyase activity of CYP17A1 is essential [21]. Thus, inhibition of the 17,20-lyase activity of CYP17A1 might be a rational approach to inhibit extragonadal androgen production and prostate cancer progression. In this regard, the antifungal agent ketoconazole possesses CYP17A1 inhibitory activity [22] and has been tested clinically in patients with CRPC. However, ketoconazole treatment is often discontinued due to toxicity which stems from its ability to potently inhibit the activity of other CYP enzymes in addition to CYP17A1 [22] and then usefulness of CYP17A1 inhibitor for CRPC was not fully established. More recently the steroid analogue abiraterone acetate, a more specific CYP17A1 inhibitor, has been reported to show clinically significant antitumor activity in up to 70% of prostate cancer patients [23], [24]. We have generated a series of non-steroidal, naphthylmethylimidazole derivatives expressly designed to specifically inhibit the 17,20-lyase activity of human CYP17A1 to reduce impact on steroid levels other than androgen, which originally targeted hormone-dependent prostate cancer. Preliminary studies to assess potency and specificity of this series have identified the lead analogue, orteronel (TAK-700) (6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl]-N-methyl-2-naphthamide [25] (Fig. 1), as a potential clinical candidate.