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

MYC amplification is frequently observed in approximately 50% of human cancers, rendering it a highly desired anticancer target. Given the challenge of direct pharmacological inhibiting of MYC, impairing the interaction of MYC and its key cofactor WDR5 has been proposed as a promising strategy for MYC-driven cancer treatment. Herein, we report the discovery of 5-thiocyanatothiazol-2-amines that disrupt the WDR5-MYC interaction. Hit fragments were initially identified in a fluorescence polarization (FP)-based screening of an in-house library, and structural-activity relationship exploration resulted in the lead compounds 4m and 4o with potent inhibitory activities on WDR5-MYC interaction ( K i = 2.4 μM for 4m ; K i = 1.0 μM for 4o ). These compounds were further validated via differential scanning fluorimetry (DSF) and coimmunoprecipitation (Co-IP). Moreover, 4m and 4o exhibited good cellular activities with the IC 50 values at the micromolar level (IC 50 = 0.71-7.40 μM) against multiple MYC -driven cancer cell lines. Our findings afforded a potential small molecule blocking the WDR5-MYC interaction.