Identification of 5-Thiocyanatothiazol-2-amines Disrupting WDR5-MYC Protein–Protein Interactions,ACS Medicinal Chemistry Letters

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Identification of 5-Thiocyanatothiazol-2-amines Disrupting WDR5-MYC Protein–Protein Interactions
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2024-07-01 , DOI: 10.1021/acsmedchemlett.4c00220
Haiyang Wang ₁ , Yihui Zhou _{1,

2} , Li Lu ₁ , Jie Cen ₁ , Zhenying Wu ₁ , Bo Yang _{1,

3,

4} , Chengliang Zhu _{1,

3,

5,

6} , Ji Cao _{1,

3,

4,

7} , Yongping Yu _{1,

7,

8} , Wenteng Chen _{1,

7}

Affiliation

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.

中文翻译：

鉴定破坏 WDR5-MYC 蛋白质-蛋白质相互作用的 5-硫氰酸噻唑-2-胺

MYC扩增经常在大约 50% 的人类癌症中观察到，使其成为非常理想的抗癌靶点。鉴于直接药理抑制 MYC 的挑战，削弱 MYC 及其关键辅因子 WDR5 的相互作用已被提议作为 MYC 驱动的癌症治疗的一种有前景的策略。在此，我们报告了破坏 WDR5-MYC 相互作用的 5-硫氰酸噻唑-2-胺的发现。命中片段最初是在内部文库基于荧光偏振 (FP) 的筛选中鉴定出来的，结构-活性关系探索产生了对 WDR5-MYC 相互作用具有有效抑制活性的先导化合物4m和4o ( K _i = 2.4 μM 为4m ； K _i = 1.0 μM 为4o )。这些化合物通过差示扫描荧光法 (DSF) 和免疫共沉淀 (Co-IP) 得到进一步验证。此外， 4m和4o对多种MYC驱动的癌细胞系表现出良好的细胞活性，IC ₅₀值在微摩尔水平（IC ₅₀ = 0.71–7.40 μM）。我们的研究结果提供了一种潜在的阻断 WDR5-MYC 相互作用的小分子。

更新日期：2024-07-01

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