Spires Thomas E, Fink Brian E, Kick Ellen K, You Dan, Rizzo Cheryl A, Takenaka Ivone, Lawrence R Michael, Ruan Zheming, Salvati Mark E, Vite Gregory D, Weinmann Roberto, Attar Ricardo M, Gottardis Marco M, Lorenzi Matthew V
Oncology Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Prostate. 2005 Oct 1;65(2):159-70. doi: 10.1002/pros.20279.
Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate.
In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone.
Initial screening efforts identified a natural product, 18beta-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription.
The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.
前列腺癌（PCa）的内分泌治疗依赖于能够破坏睾丸中睾酮生物合成和/或通过直接拮抗活性激素作用于激素作用的非性腺靶组织（如前列腺）中的雄激素受体（AR）的药物。
为了评估可抑制性腺或非性腺睾酮生物合成的新疗法，我们开发了高通量生化和细胞筛选试验，以鉴定17β-羟基类固醇脱氢酶III型（17β-HSD3）的抑制剂，该酶催化雄烯二酮（AdT）转化为睾酮。
初步筛选发现一种天然产物18β-甘草次酸和一种新型AdT衍生物3-O-苄基雄甾酮是该酶的有效抑制剂。进一步的研究导致鉴定出几类非甾体低分子量化合物，它们能有效抑制17β-HSD3的酶活性。最有效的17β-HSD3抑制剂类别之一是从与核激素受体非甾体调节剂相关的化合物集合中鉴定出的一系列邻氨基苯甲酰胺小分子。基于邻氨基苯甲酰胺的17β-HSD3抑制剂以BMS-856为例，该化合物对17β-HSD3酶活性的抑制作用低至纳摩尔水平。此外，这一系列化合物对17β-HSD3介导的AdT细胞转化为睾酮具有强效抑制作用，并抑制了促进AR依赖性转录所需的17β-HSD3介导的睾酮转化。
鉴定17β-HSD3的非甾体功能性抑制剂可能是一种有用的补充方法，用于在PCa治疗中破坏睾酮生物合成。
