Searching for novel MDM2/MDMX dual inhibitors through a drug repurposing approach.

Autor: Li K; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Hu W; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Wang Y; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Chen W; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Wen H; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Liu J; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Li W; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China., Wang B; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Jazyk: angličtina
Zdroj: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2024 Dec; Vol. 39 (1), pp. 2288810. Date of Electronic Publication: 2023 Dec 07.
DOI: 10.1080/14756366.2023.2288810
Abstrakt: Disruption of p53-MDM2/MDMX interaction by smaller inhibitors is a promising therapeutic intervention gaining tremendous interest. However, no MDM2/MDMX inhibitors have been marketed so far. Drug repurposing is a validated, practical approach to drug discovery. In this regard, we employed structure-based virtual screening in a reservoir of marketed drugs and identified nintedanib as a new MDM2/MDMX dual inhibitor. The computational structure analysis and biochemical experiments uncover that nintedanib binds MDM2/MDMX similarly to RO2443, a dual MDM2/MDMX inhibitor. Furthermore, the mechanistic study reveals that nintedanib disrupts the physical interaction of p53-MDM2/MDMX, enabling the transcriptional activation of p53 and the subsequent cell cycle arrest and growth inhibition in p53 +/+ cancer cells. Lastly, structural minimisation of nintedanib yields H3 with the equivalent potency. In summary, this work provides a solid foundation for reshaping nintedanib as a valuable lead compound for the further design of MDM2/MDMX dual inhibitors.
Databáze: MEDLINE