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

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

  • ACS Med Chem Lett. 2024 Jul 1;15(7):1143-1150. 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 8 7,  Wenteng Chen 1 7
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 3 Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou 310000, China.
  • 4 Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou 310020, China.
  • 5 Center for Drug Safety Evaluation and Research of ZJU, Hangzhou 310058, China.
  • 6 Cancer Center, Zhejiang University, Hangzhou City 310058, China.
  • 7 Jinhua Institute of Zhejiang University, Jinhua 321299, China.
  • 8 School of Pharmacy, Xinjiang Medical University, Urumqi 830054, China.
PMID: 39015274 DOI: 10.1021/acsmedchemlett.4c00220
Abstract

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.

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