Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer

Abstract

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation. KEYWORDS: Prostate cancer, CYP17A1, benzimidazoles, lyase, CYP11B1, CYP21A2, cortisol P rostate cancer (CaP) is the second leading cause of cancer death in men in the United States.1 An estimated 220,800 new cases are expected to be diagnosed in 2015 with 1 in 30 dying of this metastatic disease. Since Huggins and Hodges made the observation over 70 years ago that the growth and survival of prostate cancer is fueled by the presence of androgens, 2 androgen deprivation therapy (ADT) became the first line of treatment for men afflicted by CaP. 3 In particular, chemical castration with a luteinizing hormone-releasing hormone such as Lupron is a commonly accepted and effective initial method of treatment. 4 Unfortunately, this therapy only reduces the circulating levels of testosterone by 90%, which originates from the testes, and it does not affect the remaining 10% of testosterone produced by the adrenal glands.5 Within 19 months, the androgen receptor will engage in a heightened sensitivity to the presence of low levels of testosterone and other androgens as well as progesterone, causing a reemergence of cancer growth to appear and an inevitable progression to castration-resistant prostate cancer (CRPC).6 As a result of the severity of this disease, new therapies have been highly coveted for this urgent and unmet medical need.Limited options to treat CRPC have warranted new research developments in this area. Until recently, chemotherapy with docetaxel was the only second-line therapy to improve the overall survival of prostate cancer patients followed by ketoconazole (Nizoral), an antifungal agent that can ameliorate some of the symptoms of prostate cancer through nonselective CYP inhibition (Figure 1). 6,7 However, the overwhelming toxicity associated with each of these treatments relegates their use to short-term in any medicinal regimen. Recent approval of abiraterone acetate (Zytiga) 8 by the FDA for postchemotherapy use represents a major breakthrough and allows for the near elimination of the remaining 10% testosterone produced by the adrenal glands that can promote and sustain CRPC.

Promising Tools in Prostate Cancer Research: Selective Non-Steroidal Cytochrome P450 17A1 Inhibitors

“…Another compound, abiraterone, effectively inhibits CYP17A1 ( Table 1 ), but it also binds several drug metabolizing cytochrome P450 enzymes including CYP3A4 and CYP2D6 which may lead to adverse effects and toxicities 9 . Furthermore, abiraterone inhibits CYP21A2 30 and CYP11B1 9 which in the clinical setting, forces co-administration of prednisone to mitigate the resulting mineralocorticoid excess 30 . Besides the effects from the binding of abiraterone to CYP enzymes, it may have several other anticancer effects, involving binding to the androgen receptor, 3β‐hydroxysteroid dehydrogenase inhibition as well as decreasing the levels of heat shock protein 27, a cytoprotective agent involved in drug resistance issues, in androgen-insensitive prostate cancer cells 31 .…”

Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2

“…Other experimental therapeutics being developed in this class include the abiraterone analog galeterone 6, 7 and the non-steroidal orteronel, 8 VT-464, 9 and BMS-351. 10…”

Androgen signaling regulates the transcription of anti-Müllerian hormone via synergy with SRY-related protein SOX9A

“…More specifically, CYP17A1 acts on pregnenolone and progesterone to add a hydroxyl (AOH) group at carbon 17 of the steroid D ring (the hydroxylase activity), or acts upon 17-hydroxyprogesterone and 17-hydroxypregnenolone to split the side-chain off the steroid nucleus (the lyase activity) [25]. The selective CYP17A1 lyase inhibitor BMS-351, which is used to treat prostate cancer, has been discovered recently [26].…”