Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Cell Chem Biol. 2017 Jul 20;24(7):825-832.e6. doi: 10.1016/j.chembiol.2017.05.020. Epub 2017 Jun 22.
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ,3β-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3β-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5β-reduced metabolites. D4G inhibits steroidogenesis and suppresses AR protein stability, AR target gene expression, and xenograft growth comparably with galeterone, and further conversion by SRD5A leads to loss of several activities that inhibit the androgen axis that may compromise clinical efficacy. Together, these findings define a critical metabolic class effect of steroidal drugs with a Δ,3β-hydroxyl structure.
加特勒酮是一种甾体 CYP17A1 抑制剂、雄激素受体 (AR) 拮抗剂和 AR 降解剂，正在进行用于治疗去势抵抗性前列腺癌 (CRPC) 的 III 期临床试验。加特勒酮的 A/B 甾体环 (Δ,3β-羟基) 结构与胆固醇相同，这使得具有相同结构的内源性类固醇（如脱氢表雄酮和孕烯醇酮）成为 3β-羟甾脱氢酶 (3βHSD) 的底物。我们发现加特勒酮被 3βHSD 代谢为 Δ-加特勒酮 (D4G)，D4G 进一步被甾体 5α-还原酶 (SRD5A) 转化为 3-酮-5α-加特勒酮 (5αG)、3α-OH-5α-加特勒酮和 3β-OH-5α-加特勒酮；在体内，它也被转化为三种相应的 5β-还原代谢物。D4G 抑制类固醇生成，并抑制 AR 蛋白稳定性、AR 靶基因表达和异种移植物生长，与加特勒酮相当，进一步由 SRD5A 转化会导致丧失几种抑制雄激素轴的活性，这可能会影响临床疗效。综上所述，这些发现定义了具有 Δ,3β-羟基结构的甾体药物的关键代谢类效应。
