Searching for novel MDM2/MDMX dual inhibitors through a drug repurposing approach
AbstractDisruption 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 st...
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| Main Authors: | , , , , , , , |
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| Format: | Book |
| Published: |
Taylor & Francis Group,
2024-12-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | AbstractDisruption 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. |
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| Item Description: | 10.1080/14756366.2023.2288810 1475-6374 1475-6366 |