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 - 22/03/24
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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | WS-384 dually targets LSD1 and DCN1-UBC12 interactions. |
• | WS-384 showed excellent anti-tumor effect on NSCLC in vitro and in vivo. |
• | Upregulation of p21 is the synergistic effect of dual targets of WS-384. |
• | The synergetic upregulation of p21 contributes to the anti-tumor effect of WS-384. |
Keywords : LSD1, DCN1, Non-small cell lung cancer, Cancer therapy
Plan
Vol 173
Article 116240- avril 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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