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),[1] but nutlin-3 is most commonly used in anti-cancer studies.[2] Nutlins disrupt the p53–MDM2 interaction by occupying a p53-binding pocket of MDM2.[3] Many tumors that express normal p53 and normal or elevated levels of MDM2 may be targeted using nutlin.[3] Nutlin-3 acts quickly in vitro, leading to increased levels of p53 protein within minutes.[4]

The more potent of the two enantiomers, nutlin-3a ((–)-nutlin-3), can be synthesized in a highly enantioselective fashion.[5] 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.[6][7] Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.[8][9][10] 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. [11]

## References

1. ↑ "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science 303 (5659): 844–848. February 2004. doi:10.1126/science.1092472. PMID 14704432. Bibcode: 2004Sci...303..844V.
2. ↑ "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 49: 223–241. 2008. doi:10.1146/annurev.pharmtox.48.113006.094723. PMID 18834305.
3. ↑ 3.0 3.1 "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 103 (6): 1888–1893. February 2006. doi:10.1073/pnas.0507493103. PMID 16443686.
4. ↑ "Mechanism-specific signatures for small-molecule p53 activators". Cell Cycle (Landes Bioscience) 10 (10): 1590–1598. May 2011. doi:10.4161/cc.10.10.15519. PMID 21490429.
5. ↑ "Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor". Chemical Science 2 (6): 1076–1079. January 2011. doi:10.1039/C1SC00061F. PMID 22708054.
6. ↑ Liu, Yanqing; Su, Zhenyi; Tavana, Omid; Gu, Wei (2024-06-10). "Understanding the complexity of p53 in a new era of tumor suppression" (in English). Cancer Cell 42 (6): 946–967. doi:10.1016/j.ccell.2024.04.009. ISSN 1535-6108. PMID 38729160. PMC 11190820. https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00133-8.
7. ↑ "Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells". Cancers 10 (11): 396. October 2018. doi:10.3390/cancers10110396. PMID 30352966.
8. ↑ "Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors" (in en). Medicinal Chemistry Research 30 (12): 2216–2227. December 2021. doi:10.1007/s00044-021-02802-w. ISSN 1054-2523.
9. ↑ "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 29 (16): 2364–2368. August 2019. doi:10.1016/j.bmcl.2019.06.007. PMID 31196710.
10. ↑ "Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core". Pharmaceuticals 15 (4): 444. April 2022. doi:10.3390/ph15040444. PMID 35455441.
11. ↑ "The evolution of Nutlins as p53-MDM2 inhibitors". Medicinal Chemistry Research. doi:10.1007/s00044-025-03492-4.

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