2. Academic Validation
  3. The discovery of potent USP2/USP8 dual-target inhibitors for the treatment of breast cancer via structure guided optimization of ML364

The discovery of potent USP2/USP8 dual-target inhibitors for the treatment of breast cancer via structure guided optimization of ML364

  • Eur J Med Chem. 2024 Mar 15:268:116275. doi: 10.1016/j.ejmech.2024.116275.
Yucheng Tian 1,  Kang Liu 1,  Dongdong Wu 1,  Liuyi Wu 1,  Qianqian Xu 1,  Wei Wei 1,  Zhiyu Li 2,  Qianming Du 3,  Jinlei Bian 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 3 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, PR China; School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: [email protected].
PMID: 38452725 DOI: 10.1016/j.ejmech.2024.116275
Abstract

USP2 and USP8 are crucial in the development and progression of breast Cancer, primarily through the stabilization of protein substrates such as Her2 and ERα. The dual-target inhibitor ML364, targeting both USP2 and USP8, has garnered significant interest in recent research. In this study, we developed a series of ML364 derivatives using ligand-based drug design strategies. The standout compound, LLK203, demonstrated enhanced inhibitory activity, showing a 4-fold increase against USP2 and a 9-fold increase against USP8, compared to the parent molecule. In MCF-7 breast Cancer cells, LLK203 effectively degraded key proteins involved in Cancer progression and notably inhibited cell proliferation. Moreover, LLK203 exhibited potent in vivo efficacy in the 4T1 homograft model, while maintaining a low toxicity profile. These results underscore the potential of LLK203 as a promising dual-target inhibitor of USP2/USP8 for breast Cancer treatment.

Keywords

Breast cancer; Estrogen receptor alpha; Her2; USP2/USP8 inhibitors.

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