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Steroid sulfatase: A systematic study on the isolation, single step purification, and identification of its new
Naveera Zafar1, Humaira Zafar2, Sumaira Javaid1
1Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
Abstract:
Estrogen receptor positive breast cancer (ERBC) is among the most common type of breast cancers. Currently aromatase inhibition is the mainstay therapy of ERBC. However, the emergence of drug resistance, and relapse of tumor progression has created the need of identification of new targets for drug development against ERBC. Hence, steroid sulfatase (STS) has emerged as a new drug target for the treatment of ERBC, as it is involved in the biosynthesis of hormones, including estrogens and androgens. The current study focuses on the purification of STS from human placentae, followed by identification of its small molecule inhibitors. STS enzyme was purified from human placenta, and characterized by Q-TOF LC/MS. The catalytic activity of the enzyme was analyzed using 1H NMR spectroscopy. Afterwards, a total of 161 commercially available synthetic and natural products were screened using fluorescence-based inhibition assay in-vitro. Among them, compounds 1 (sulfochlorophenol S), 2 (1,2-dihyrdoxyanthracene-9,10-dione), 3 (phenyl-2,3,4-trihydroxyphenyl methanone), 4 (4-anilinophenol), and 5 (lawsone) showed a moderate STS inhibitory activity with IC50 values between 11 and 16 μM. The non-covalent interactions between inhibitors and STS were studied via STD-NMR, molecular docking, and simulation studies. The newly identified inhibitors were found to be non-cytotoxic and druggable as assessed via MTT calorimetric, and ADMET analyses. The current study identifies significant and non-cytotoxic inhibitors of STS as potential drug hit against ERBC.
Insights
New research identifies potential drug candidates targeting steroid sulfatase (STS) for estrogen receptor-positive breast cancer (ERBC). These non-cytotoxic inhibitors offer a promising avenue for developing novel therapies against drug-resistant ERBC.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Estrogen receptor-positive breast cancer (ERBC) is a prevalent malignancy.
- Current therapies like aromatase inhibition face challenges due to drug resistance and tumor relapse.
- Steroid sulfatase (STS) is implicated in hormone biosynthesis and represents a novel therapeutic target for ERBC.
Purpose of the Study:
- To purify and characterize steroid sulfatase (STS) from human placenta.
- To identify and validate small molecule inhibitors of STS with potential therapeutic applications against ERBC.
Main Methods:
- STS purification from human placenta and characterization using Q-TOF LC/MS.
- Enzyme activity assay using 1H NMR spectroscopy.
- In vitro screening of 161 compounds using fluorescence-based inhibition assays, followed by STD-NMR, molecular docking, and ADMET analyses.
Main Results:
- Five compounds (sulfochlorophenol S, 1,2-dihyd rox yanthracene-9,10-dione, phenyl-2,3,4-trihydroxyphenyl methanone, 4-anilinophenol, and lawsone) exhibited moderate STS inhibitory activity (IC50: 11-16 μM).
- Non-covalent interactions between inhibitors and STS were elucidated.
- Identified inhibitors demonstrated non-cytotoxicity and favorable druggability profiles.
Conclusions:
- The study successfully identified novel, non-cytotoxic small molecule inhibitors of STS.
- These compounds represent promising drug hits for the development of new treatments for ERBC, potentially overcoming existing resistance mechanisms.
