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  • The knowledge on the structure

    2024-06-07

    The knowledge on the structure of CYP17, including its active site, provides a rationale for understanding many mutations that are found in enzyme dysfunction in clinical disease as well as the enzyme's dual hydroxylase and lyase catalytic capabilities. This knowledge will assist rational drug design particularly aiming the development of compounds that selectively inhibits CYP17A1 and particularly only its lyase activity, allowing an improvement in the treatment of prostate and other hormone-responsive cancers [112]. In spite of the 3D structure of the CYP17 is unavailable, structure–activity analysis has revealed the general features of a good inhibitor and recent docking and modeling studies have further shed some light on the way these molecules interact with the enzyme's active site [112], [113]. Quite recently, DeVore et al. reported an important advance in this context with the publication of the X-ray crystal structures of CYP17 obtained in the presence of potent steroidal inhibitors [113].
    Steroidal inhibitors of 17α-hydroxylase/17,20-lyase (CYP17) The classical approach to treat hormone-dependent PC is systemic ablation of androgen by castration, either surgical or chemical [18]. However, after 18–24 months following the onset of primary hormonal therapies, the disease becomes androgen-refractory by mechanisms in which AR-mediated signaling and gene gyy is still active despite castrate androgen levels [24], [25]. At this point, the malignant disease is considered castrate-resistant PC (CRPC), previously named hormone-refractory PC (HRPC). The standard clinical approach for the treatment of CRPC is the combination of docetaxel (153) (Taxotere®) (Fig. 10) and prednisone, which improves survival time in about 18 months [114], [115]. Another therapeutic strategy for advanced PC comprises the use of ketoconazol (155), an azole antifungal CYP17 inhibitor, however in the doses needed to successfully inhibit the androgen production, serious side-effects limit its use [116], [117]. Invasive and metastatic PC lesions often exhibit a partial and time-limited response to therapy before the cancer progress and patient succumbs to the disease. In the past few year novel therapies for CRPC have been developed, which brought a light of hope for cancer patients [118], [119]. Cabazitaxel (154) (Jevtana®) [120] (Fig. 10), a novel taxane derivative, has been recently approved for metastatic CRPC (mCRPC), which has progressed following docetaxel therapy, whereas the immunotherapy Sipuleucel-T (Provenge®) has been approved for the treatment of asymptomatic or minimally symptomatic mCPRC. In April 2011, abiraterone acetate (156) (Zytiga®) (Fig. 10) became the first steroidal CYP17 inhibitor to be approved by the FDA for the treatment of docetaxel-resistant mCRPC [121], [122], [123], [124], [125]. Enzalutamide (158) (Xtandi®) [126] an androgen receptor (AR) antagonist that prevents androgens to binding the AR and nuclear translocation and co-activator recruitment of the ligand-receptor complex has been approved by the FDA, in August of 2012, for the treatment of CRPC. Galeterone (TOK-001, former VN/124-1) (159), another steroidal CYP17 inhibitor, with AR antagonistic and ablative activities, is currently undergoing Phase I/II clinical trials for the treatment of chemotherapy-naive CRPC [127], [128]. Other compounds undergoing clinical trial in PC patients include TAK-700 (160), a non-steroidal imidazole CYP17 inhibitor [129], among several newer cytotoxic drugs and anti-angiogenic compounds [130]. These last achievements with abiraterone (157) and galeterone (159) made over the past couple of years have raised the interest on CYP17 inhibitors, which are generally classified as steroidal and non-steroidal agents [4], [18], [129], [131], [132]. The first reports on steroidal CYP17 inhibitors date back to about 40 years ago [4]. Steroidal inhibitors are based on the structure of pregnenolone (1) and progesterone (2), the natural substrates of CYP17 enzyme. The steroid core has been chemically modified, mainly at C17, in order to increase its ability to interact with the enzyme active site [4], [18], [75], [131], [132].