SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects.
SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects.
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硫酸化途径：通过芳基氨基磺酸盐抑制类固醇硫酸酯酶：临床进展、机制和未来前景。
DOI：
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发表时间：
2018
影响因子：
3.5
通讯作者：
B. Potter
中科院分区：
文献类型：
--
作者：
B. Potter
类固醇硫酸酯酶是激素依赖性疾病内分泌治疗的新兴药物靶点，催化硫酸雌激素水解为雌激素。药物发现，开发核心芳基 O-氨基磺酸盐药效基团，已导致甾体和非甾体药物进入大量临床试验，在肿瘤学和女性健康方面取得了有希望的结果。类固醇雌激素氨基磺酸衍生物是第一种不可逆的活性位点定向抑制剂，在临床上开发为口服雌二醇前药并用于子宫内膜异位症。这篇综述总结了硫酸酯酶抑制治疗概念的研究工作、迄今为止执行的临床试验以及对类固醇硫酸酯酶抑制机制的新见解。迄今为止，非甾体硫酸酯酶抑制剂伊罗司他已在乳腺癌、子宫内膜癌和前列腺癌中单独或联合进行临床评估。多功能核心药效团通过三种不同的作用机制赋予有吸引力的药物特性和功能，作为前药、酶活性位点修饰基序（可能通过直接氨磺酰基转移），以及作为增强活性的结构成分，例如通过增强微管蛋白秋水仙碱结合位点的相互作用。铜绿假单胞菌芳基硫酸酯酶的初步新结构数据表明，两种可能的基于氨基磺酸盐的加合物与活性位点甲酰甘氨酸作为通过氨磺酰或磺酰胺转移抑制最终产物的候选物，并提出了推测性选择。调查了硫酸酯酶抑制的临床状况及其未来的发展情况。还讨论了双靶向方法、2-取代甾体氨基磺酸盐和非甾体衍生物作为激素非依赖性肿瘤多靶向药物的开发以及其他新兴方向。
Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core aryl O-sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women's health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on the Pseudomonas aeruginosa arylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone-independent tumours, with other emerging directions.
第一个类固醇硫酸酯酶 (STS) 和 17β-羟基类固醇脱氢酶 1 型 (17β-HSD1) 双重抑制剂：设计多种配体作为雌激素依赖性疾病的新型潜在疗法
影响因子：
7.3
作者：
Abdelsamie;Frotscher
通讯作者：
Frotscher
DOI：
10.1056/nejmoa1604700
发表时间：
2016-07-21
期刊：
The New England journal of medicine
影响因子：
--
作者：
Goss PE;Ingle JN;Pritchard KI;Robert NJ;Muss H;Gralow J;Gelmon K;Whelan T;Strasser-Weippl K;Rubin S;Sturtz K;Wolff AC;Winer E;Hudis C;Stopeck A;Beck JT;Kaur JS;Whelan K;Tu D;Parulekar WR
通讯作者：
Parulekar WR
具有多种作用模式的靶向 NF1 癌症疗法：类似于天然抗癌代谢物 2-甲氧基雌二醇的小分子激素样药物。
影响因子：
8.8
作者：
Shen,Yu-chi;Upadhyayula,Ravi;Cevallos,Stephanie;Messick,RyanJ;Hsia,Tammy;Leese,MathewP;Jewett,DouglasM;Ferrer-Torres,Daysha;Roth,ThereseM;Dohle,Wolfgang;Potter,BarryVL;Barald,KateF
通讯作者：
Barald,KateF