17β-Hydroxysteroid Dehydrogenase Type 1 Inhibition: A Potential Treatment Option for Non-Small Cell Lung Cancer

Abstract

In the face of the clinical challenge posed by non-small cell lung cancer (NSCLC), the present need for new therapeutic approaches is genuine. Up to now, no proof existed that 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a viable target for treating this disease. Synthesis of a rationally designed library of 2,5-disubstituted furan derivatives followed by biological screening led to the discovery of 17β-HSD1 inhibitor 1, capable of fully inhibiting human NSCLC Calu-1 cell proliferation. Its pharmacological profile renders it eligible for further in vivo studies. The very high selectivity of 1 over 17β-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17β-HSD1 and 1 hold promise in fighting NSCLC.

Dual Targeting of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential Therapeutic Option for the Treatment of Endometriosis

“…In addition, they displayed low to moderate selectivity over 17β-HSD2, see Chart 1. 74 Therefore, the lead for the present was a hydroxyphenylfurancarboxamide scaffold recently reported by our group (compound B, Chart 1) 91 that showed better selectivity (SF = 563 for B vs 33 for A) and higher metabolic stability than A (half-life in human liver S9 fraction 38 min for B vs less than 5 min for A).…”

“…Many new Chart 1. First Dual STS/17β-HSD1 Inhibitor (A) 74 and 17β-HSD1 Inhibitor (B), 91 Reported by Our Group a a Experimental data are derived from previous publications of the authors. 74,91 H17β-HSD1: human 17β-HSD1, hS9 and mS9: human and mouse liver S9 fraction, S.F.…”

“…First Dual STS/17β-HSD1 Inhibitor (A) 74 and 17β-HSD1 Inhibitor (B), 91 Reported by Our Group a a Experimental data are derived from previous publications of the authors. 74,91 H17β-HSD1: human 17β-HSD1, hS9 and mS9: human and mouse liver S9 fraction, S.F. : selectivity factor = cell-free hIC 50 (17β-HSD2)/hIC 50 (17β-HSD1), n.i: no inhibition (<10% inhibition at 1 μM).…”

Potent Dual Inhibitors of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 with a Suitable Pharmacokinetic Profile for In Vivo Proof-of-Principle Studies in an Endometriosis Mouse Model

“…Another class of 17β-HSD1 inhibitors that has been recently discovered by our group seems to be more promising concerning metabolic stability and selectivity over the type 2 enzyme . This class is based on a hydroxyphenyl furan carboxamide scaffold.…”

“…Another class of 17β-HSD1 inhibitors that has been recently discovered by our group seems to be more promising concerning metabolic stability and selectivity over the type 2 enzyme. 23 This class is based on a hydroxyphenyl furan 1), has exceptionally high selectivity over 17β-HSD2, and very promising metabolic stability data, which might be linked to the fact that the free hydroxy phenol is not easily accessed by the metabolizing enzymes of phase II as it is sterically protected by the two adjacent methyl groups.…”