First-of-its-kind STARD₃ Inhibitor: In Silico Identification and Biological Evaluation as Anticancer Agent

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Steroidogenic acute regulatory protein-related lipid transfer (START) domain containing 3 (STARD3) is overexpressed in various cancers, including breast, colorectal, gastric, and prostate cancers.
• STARD3 is a potential therapeutic target due to its role in cancer development, yet no inhibitors have been identified to date.

Purpose of the Study:

• To identify the first inhibitor of STARD3 using computational strategies.
• To characterize the binding mode of cholesterol into STARD3.
• To develop a pharmacophore-based virtual screening protocol for STARD3 inhibitor discovery.

Main Methods:

• In silico prediction of cholesterol binding mode to STARD3.
• Pharmacophore-based virtual screening to identify potential inhibitors.
• In vitro assays to determine binding affinity (IC₅₀) and antiproliferative activity.
• Cellular assays to confirm STARD3 targeting and degradation.

Main Results:

• The first STARD3 inhibitor, VS1, was identified with a micromolar affinity (IC₅₀ = 35 μM).
• VS1 demonstrated antiproliferative activity against breast (MCF7, MDA-MB-231) and colon (HCT-116) cancer cell lines (IC₅₀ = 49.7–105.5 μM).
• VS1 specifically targets STARD3 within cells, leading to its degradation, despite moderate potency.

Conclusions:

• The study successfully identified the first STARD3 inhibitor, VS1, validating the computational approaches used.
• VS1 serves as a crucial starting point for developing more potent STARD3 inhibitors for cancer therapy.
• The findings highlight STARD3 as a druggable target with potential therapeutic implications for multiple cancer types.