2. Academic Validation
  3. Discovery of WS-384, a first-in-class dual LSD1 and DCN1-UBC12 protein-protein interaction inhibitor for the treatment of non-small cell lung cancer

Discovery of WS-384, a first-in-class dual LSD1 and DCN1-UBC12 protein-protein interaction inhibitor for the treatment of non-small cell lung cancer

  • Biomed Pharmacother. 2024 Apr:173:116240. doi: 10.1016/j.biopha.2024.116240.
Anqi Li 1,  Ting Ma 2,  Shuai Wang 1,  Yueyang Guo 1,  Qianqian Song 1,  Hongmin Liu 3,  Bin Yu 4,  Siqi Feng 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
  • 2 School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 3 School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China. Electronic address: liuhm@zzu.edu.cn.
  • 4 School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China. Electronic address: yubin@zzu.edu.cn.
  • 5 School of Pharmaceutical Sciences & Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China. Electronic address: fsq1212@zzu.edu.cn.
PMID: 38401512 DOI: 10.1016/j.biopha.2024.116240
Abstract

Abnormally high expression of lysine-specific demethylase 1 A (LSD1) and DCN1 plays a vital role in the occurrence, development, and poor prognosis of non-small cell lung Cancer (NSCLC). Accumulating evidence has shown that the development of small-molecule inhibitors dually targeting LSD1 and the DCN1-UBC12 interaction probably have therapeutic promise for Cancer therapy. This work reported that WS-384 dually targeted LSD1 and DCN1-UBC12 interactions and evaluated its antitumor effects in vitro and in vivo. Specifically, WS-384 inhibited A549 and H1975 cells viability and decreased colony formation and EdU incorporation. WS-384 could also trigger cell cycle arrest, DNA damage, and Apoptosis. Moreover, WS-384 significantly decreased tumor weight and volume in A549 xenograft mice. Mechanistically, WS-384 increased the gene and protein level of p21 by suppressing the neddylation of cullin 1 and decreasing H3K4 demethylation at the CDKN1A promoter. The synergetic upregulation of p21 contributed to cell cycle arrest and the proapoptotic effect of WS-384 in NSCLC cells. Taken together, our proof of concept studies demonstrated the therapeutic potential of dual inhibition of LSD1 and the DCN1-UBC12 interaction for the treatment of NSCLC. WS-384 could be used as a lead compound to develop new dual LSD1/DCN1 inhibitors for the treatment of human diseases in which LSD1 and DCN1 are dysregulated.

Keywords

Cancer therapy; DCN1; LSD1; Non-small cell lung cancer.

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