First Dual Inhibitors of Steroid Sulfatase (STS) and 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1): Designed Multiple Ligands as Novel Potential Therapeutics for Estrogen-Dependent Diseases

STS
and 17β-HSD1 are attractive targets for the treatment
of estrogen-dependent diseases like endometriosis and breast cancer.
The simultaneous inhibition of both enzymes appears more promising
than blockage of either protein alone. We describe a designed multiple
ligand approach resulting in highly potent dual inhibitors. The most
interesting compound 9 showed nanomolar IC50 values for both proteins, membrane permeability, and no interference
with estrogen receptors. It efficiently reversed E1S- and E1-induced
T47D cell proliferation.

类固醇硫酸酯酶（STS）与17β-羟基类固醇脱氢酶1（17β-HSD1）均为治疗子宫内膜异位症、乳腺癌等雌激素依赖性疾病的极具开发潜力的药物靶点。同时抑制这两种酶的策略，相较单独阻断任一蛋白而言，更具应用前景。本研究报道了一种经设计的多配体研发策略，可获得高效能的双重抑制剂。其中最具研究价值的化合物9，对两种靶蛋白均展现出纳摩尔级的半最大抑制浓度（IC50），同时具备膜通透性，且不会对雌激素受体产生干扰。该化合物可有效逆转雌酮硫酸酯（E1S）与雌酮（E1）诱导的T47D细胞增殖。