Novel inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and steroid sulfatase (STS) with unique dual mode of action : potential drugs for the treatment of non-small cell lung cancer (NSCLC) and endometriosis

Estrogens, in particular estradiol‎ (E2)‎ play an important role in estrogen-dependent diseases (EDDs), such as non-small-cell lung cancer ‎‎(NSCLC) and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is frequently expressed in NSCLC tissues, leading to cancer development and progression. Thus, the first objective of this study (chapter 3.1) is the development of a novel series of highly potent non-steroidal, selective ‎‎17β-HSD1 inhibitors in order to enhance the treatment of NSCLC. ‎ This section of the study showed that 17β-HSD1 is a promising therapeutic target for NSCLC, providing new avenues for the treatment of this lethal cancer. Steroid sulfatase (STS) and 17β-HSD1 are promising targets for the treatment of endometriosis because they ‎limit estrogen formation mainly in the target cells, leading to fewer ‎side effects. ‎Thus, the second part of the study ‎(chapter 3.2) ‎aims at developing dual inhibitors of STS and 17β-HSD1, which provide a novel treatment option. The synthesized sulfamates should be drugs for inhibition of STS, and prodrugs for 17β-HSD1 inhibition. The most active compounds of this part showed nanomolar IC50 values for STS in cellular assays ‎and their corresponding phenols displayed potent 17β-HSD1 inhibition in cell-free and cellular ‎assays as well as high selectivity over 17β-HSD2. These findings suggest that the “drug-prodrug concept” ‎has been applied successfully ‎(chapter 3.2).