Wang Haiyang, Zhou Yihui, Lu Li, Cen Jie, Wu Zhenying, Yang Bo, Zhu Chengliang, Cao Ji, Yu Yongping, Chen Wenteng
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
ACS Med Chem Lett. 2024 Jul 1;15(7):1143-1150. doi: 10.1021/acsmedchemlett.4c00220. eCollection 2024 Jul 11.
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 and with potent inhibitory activities on WDR5-MYC interaction ( = 2.4 μM for ; = 1.0 μM for ). These compounds were further validated via differential scanning fluorimetry (DSF) and coimmunoprecipitation (Co-IP). Moreover, and exhibited good cellular activities with the IC values at the micromolar level (IC = 0.71-7.40 μM) against multiple -driven cancer cell lines. Our findings afforded a potential small molecule blocking the WDR5-MYC interaction.
在大约50%的人类癌症中经常观察到扩增现象，这使其成为一个备受关注的抗癌靶点。鉴于直接对MYC进行药理学抑制存在挑战，破坏MYC与其关键辅因子WDR5之间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-硫氰基噻唑-2-胺的发现。最初通过基于荧光偏振（FP）的内部文库筛选鉴定出活性片段，通过构效关系探索得到了对WDR5-MYC相互作用具有强效抑制活性的先导化合物 和 （ 对 的抑制常数 = 2.4 μM； 对 的抑制常数 = 1.0 μM）。这些化合物通过差示扫描荧光法（DSF）和免疫共沉淀（Co-IP）进一步得到验证。此外， 和 对多种MYC驱动的癌细胞系表现出良好的细胞活性，其IC值处于微摩尔水平（IC = 0.71 - 7.40 μM）。我们的研究结果提供了一种潜在的可阻断WDR5-MYC相互作用的小分子。
