17β-HSD1 inhibitor(Saarland University)

Breast cancer remains a leading cause of female mortality, largely sustained by local oestrogen production. The enzyme 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1) is an enzyme involved in the oestrogen biosynthesis pathway, particularly in the conversion of estrone to estradiol, and is overexpressed in conditions such as breast cancer. Therefore, it is considered a relevant target for drug development. We evaluated phytocompounds from Annona muricata as prospective 17β‐HSD1 inhibitors through an integrated in silico workflow. Twelve reported constituents (myristic acid, myrcene, palmitic acid, hexanoic acid, pentadecane, methyl 3‐phenylpropionate, butyric acid, linalool, reticuline, phytol, camphene and calamenene) were geometry‐optimised by density‐functional theory, docked against 17β‐HSD1 (PDB 3HB5), and screened for drug‐likeness and ADMET liabilities. The top‐ranked complexes—reticuline (ΔG_pred = −8.4 kcal mol −1 ) and calamenene (−7.7 kcal mol −1 )—scored more favourably than the reference epirubicin (−5.7 kcal mol −1 ) and were subjected to 100 ns molecular‐dynamics simulations. Both ligands remained stably anchored within the catalytic pocket, with root mean square deviation (RMSD) fluctuations below 2.0 Å, yet MM‐PBSA binding free energies (reticuline −27 kJ mol −1 ; calamenene −9 kJ mol −1 ) did not surpass the reference. ADMET profiling predicted acceptable Caco‐2 permeability (0.92–0.94), and only moderate hERG liability, but also signalled potential DILI and carcinogenicity alerts that warrant caution. Reticuline and calamenene fulfilled all of Lipinski's criteria, with the exception of logP in the case of calamenene. Collectively, these findings nominate reticuline and calamenene as promising lead scaffolds for selective intracellular suppression of oestrogen biosynthesis. Experimental validation (enzyme kinetics, cell‐based assays and pharmacokinetic studies) is warranted to confirm their clinical potential in oestrogen‐dependent breast cancer.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) and steroid sulfatase (STS) are involved in the synthesis of the most potent estrogen in the human body, estradiol (E2). These enzymes are known to play a pivotal role in the progression of estrogen-dependent diseases, such as breast cancer and endometriosis. Therefore, the inhibition of 17β-HSD1 and/or STS represents a promising avenue to modulate the growth of estrogen-dependent tumors or lesions. We recently established the key role of a bromoethyl side chain added at the C3-position of a 16β-carbamoyl-benzyl-E2 nucleus to covalently inhibit 17β-HSD1. To extend the structure-activity relationship study to the C16β-position of this new selective irreversible inhibitor (PBRM), we synthesized a series of analog compounds by changing the nature of the C16β-side chain but keeping the 2-bromoethyl group at position C3. We determined their 17β-HSD1 inhibitions in T-47D cells (transformation of E1 into E2), but we did not obtain a stronger 17β-HSD1 inhibitor than PBRM. Compounds 16 and 17 were found to be more likely to bind to the catalytic site and showed a promising but moderate inhibitory activity with estimated IC₅₀ values of 0.5 and 0.7 µM, respectively (about 10 times higher than PBRM). Interestingly, adding one or two sulfamate groups in the D-ring's surroundings did not significantly decrease compounds' potential to inhibit 17β-HSD1, but clearly improved their potential to inhibit STS. These results open the door to the development of a new family of steroid derivatives with dual (17β-HSD1 and STS) inhibiting actions.