2. Academic Validation
  3. Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity

Discovery of a potent MLL1 and WDR5 protein-protein interaction inhibitor with in vivo antitumor activity

  • Eur J Med Chem. 2021 Nov 5;223:113677. doi: 10.1016/j.ejmech.2021.113677.
Weilin Chen 1,  Xin Chen 2,  Dongdong Li 2,  Xianghan Wang 2,  Guanlu Long 2,  Zhengyu Jiang 3,  Qidong You 4,  Xiaoke Guo 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jiangzhengyucpu@163.com.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: youqd@163.com.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: kexin95@126.com.
PMID: 34225179 DOI: 10.1016/j.ejmech.2021.113677
Abstract

MLL1-WDR5 interaction is essential for the formation of MLL core complex and its H3K4 methyltransferase activity. Disrupting MLL1-WDR5 interaction has been proposed as a potential therapeutic approach in the treatment of leukemia. A "toolkit" of well-characterized chemical probe will allow exploring animal studies. Based on a specific MLL1-WDR5 PPI inhibitor (DDO-2117), which was previously reported by our group, we conducted a bioisosterism approach by Click Chemistry to discover novel phenyltriazole scaffold MLL1-WDR5 interaction blockers. Here, our efforts resulted in the best inhibitor 24 (DDO-2093) with high binding affinity (Kd = 11.6 nM) and with improved drug-like properties. Both in vitro and in vivo assays revealed 24 could efficiently block the MLL1-WDR5 interaction. Furthermore, 24 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. We propose 24 as a chemical probe that is suitable for in vivo pharmacodynamic and biological studies of MLL1-WDR5 interaction.

Keywords

Antitumor; MLL1 HMT activity; MLL1-WDR5 interaction; Phenyltriazole scaffold inhibitor.

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