Identification of 5-Thiocyanatothiazol-2-amines Disrupting WDR5-MYC Protein-Protein Interactions

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• MYC amplification is prevalent in ~50% of human cancers, making it a critical therapeutic target.
• Directly inhibiting MYC is challenging; targeting its interaction with the cofactor WDR5 presents a promising alternative strategy for cancer treatment.

Purpose of the Study:

• To discover novel small molecules that inhibit the WDR5-MYC protein-protein interaction.
• To identify potent and effective inhibitors for MYC-driven cancers.

Main Methods:

• Utilized fluorescence polarization (FP)-based screening to identify initial hit fragments.
• Conducted structure-activity relationship (SAR) studies to optimize lead compounds.
• Validated WDR5-MYC interaction inhibition using differential scanning fluorimetry (DSF) and co-immunoprecipitation (Co-IP).

Main Results:

• Identified 5-thiocyanatothiazol-2-amines as inhibitors of the WDR5-MYC interaction.
• Lead compounds 4m and 4o demonstrated potent inhibition (Ki = 2.4 μM and 1.0 μM, respectively).
• Compounds 4m and 4o showed significant cellular activity (IC50 = 0.71–7.40 μM) in MYC-driven cancer cell lines.

Conclusions:

• Discovered novel small molecules targeting the WDR5-MYC interaction.
• These compounds represent a potential therapeutic approach for cancers driven by MYC.
• The findings provide a foundation for developing new drugs against MYC-dependent malignancies.