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 M...

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Published in:ACS medicinal chemistry letters 2024-07, Vol.15 (7), p.1143-1150
Main Authors: Wang, Haiyang, Zhou, Yihui, Lu, Li, Cen, Jie, Wu, Zhenying, Yang, Bo, Zhu, Chengliang, Cao, Ji, Yu, Yongping, Chen, Wenteng
Format: Article
Language:English
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Summary: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 IC50 values at the micromolar level (IC50 = 0.71–7.40 μM) against multiple MYC-driven cancer cell lines. Our findings afforded a potential small molecule blocking the WDR5-MYC interaction.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.4c00220