College of Medicine, Department of Biochemistry and Molecular Biology , University of Florida , Gainesville , Florida 32610 , United States.
Medicinal Chemistry & Drug Discovery, Department of Pharmacology , University of Oxford , Mansfield Road , Oxford OX1 3QT , U.K.
J Med Chem. 2019 Feb 28;62(4):2202-2212. doi: 10.1021/acs.jmedchem.8b01990. Epub 2019 Feb 18.
3,17β-Bis-sulfamoyloxy-2-methoxyestra-1,3,5(10)-triene (STX140), a bis-sulfamate derivative of the endogenous steroid 2-methoxyestradiol, has shown promising anticancer potency both in vitro and in vivo, with excellent bioavailability. Its activity against taxane-resistant xenografts makes it a potential drug candidate against triple-negative breast cancer (TNBC). These properties are linked to the ability of STX140 to act in a multitargeting fashion in vivo as a microtubule disruptor, leading to cell cycle arrest and with both proapoptotic and anti-angiogenic activities. Carbonic anhydrase IX (CA IX) is a well-established biomarker for aggressive cancers, including TNBC. This study reports, for the first time, the inhibitory activities of a series of steroidal and nonsteroidal sulfamate derivatives against CA IX in comparison to the ubiquitous CA II, with some compounds demonstrating 100-200-fold selectivity for CA IX over CA II. X-ray crystallographic studies of four of the most promising compounds reveal that isoform-specific residue interactions are responsible for the high specificity.
3,17β-双磺酰胺氧基-2-甲氧基雌甾-1,3,5(10)-三烯（STX140）是内源性甾体 2-甲氧基雌二醇的双磺酰胺衍生物，在体外和体内均显示出有希望的抗癌活性，具有极好的生物利用度。它对紫杉烷耐药异种移植物的活性使它成为治疗三阴性乳腺癌（TNBC）的潜在候选药物。这些特性与 STX140 作为微管破坏剂在体内以多靶点方式发挥作用的能力有关，导致细胞周期停滞，并具有促凋亡和抗血管生成活性。碳酸酐酶 IX（CA IX）是侵袭性癌症（包括 TNBC）的一个成熟的生物标志物。本研究首次报道了一系列甾体和非甾体磺酰胺衍生物对 CA IX 的抑制活性，并与普遍存在的 CA II 进行了比较，其中一些化合物对 CA IX 的选择性是 CA II 的 100-200 倍。对其中四种最有前途的化合物的 X 射线晶体学研究表明，同工型特异性残基相互作用是高特异性的原因。
