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Nutlin

Nutlins are a family of small molecule, cis-imidazoline analogs, which inhibit the interaction between MDM2 and tumor suppressor p53, stabilizing p53 and triggering cell death and senescence. Three nutlins were discovered in the initial small molecule screen (nutlin-1, nutlin-2, and nutlin-3), but nutlin-3 is most commonly used in anti-cancer studies. Nutlins disrupt the p53–MDM2 interaction by occupying a p53-binding pocket of MDM2. Many tumors that express normal p53 and normal or elevated levels of MDM2 may be targeted using nutlin. Nutlin-3 acts quickly in vitro, leading to increased levels of p53 protein within minutes.

The more potent of the two enantiomers, nutlin-3a ((–)-nutlin-3), can be synthesized in a highly enantioselective fashion. Several derivatives of nutlin, such as RG7112 and RG7388 (Idasanutlin) have been developed and progressed into human studies, but have not yet shown improved survival and may cause toxicity. Imidazoline core based on the methoxyphenyl substituents also stabilizes p53. Since its discovery in 2003, the nutlin core has been modified to obtain molecules with additional properties, such as increased solubility, irreversible MDM2 inhibitors, improved binding to MDMX, the PROTAC methodology, dual-action molecules, and fluorescent probes. {{cite journal | vauthors = Bazanov DR, Lozinskaya NA | title = The evolution of Nutlins as p53-MDM2 inhibitors | journal = Medicinal Chemistry Research

References

References

  1. (February 2004). "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science.
  2. (2008). "Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy". Annual Review of Pharmacology and Toxicology.
  3. (February 2006). "Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy". Proceedings of the National Academy of Sciences of the United States of America.
  4. (May 2011). "Mechanism-specific signatures for small-molecule p53 activators". Landes Bioscience.
  5. (January 2011). "Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor". Chemical Science.
  6. Liu, Yanqing. (2024-06-10). "Understanding the complexity of p53 in a new era of tumor suppression". Cancer Cell.
  7. (October 2018). "Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells". Cancers.
  8. (December 2021). "Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors". Medicinal Chemistry Research.
  9. (August 2019). "2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation". Bioorganic & Medicinal Chemistry Letters.
  10. (April 2022). "Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core". Pharmaceuticals.
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imidazolines 4-chlorophenyl-compounds isopropyl-compounds piperazinones methoxy-compounds ureas
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