Nutlin Explained

Nutlins are cis-imidazoline analogs which inhibit the interaction between mdm2 and tumor suppressor p53, and which were discovered by screening a chemical library by Vassilev et al. Nutlin-1, nutlin-2, and nutlin-3 were all identified in the same screen;^[1] however, Nutlin-3 is the compound most commonly used in anti-cancer studies.^[2] Nutlin small molecules occupy p53 binding pocket of MDM2 and effectively disrupt the p53–MDM2 interaction that leads to activation of the p53 pathway in p53 wild-type cells.^[3] Inhibiting the interaction between mdm2 and p53 stabilizes p53, and is thought to selectively induce a growth-inhibiting state called senescence in cancer cells. These compounds are therefore thought to work best on tumors that contain normal or "wild-type" p53. Nutlin-3 has been shown to affect the production of p53 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.^[6] Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.^{[7] [8] [9]}

Notes and References

1. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA . In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 . Science . 303 . 5659 . 844–848 . February 2004 . 14704432 . 10.1126/science.1092472 . 16132757 . 2004Sci...303..844V .
2. Shangary S, Wang S . 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 . 18834305 . 2676449 . 10.1146/annurev.pharmtox.48.113006.094723 .
3. Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT . 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 . 16443686 . 1413632 . 10.1073/pnas.0507493103 . free .
4. van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ, Laín S . Mechanism-specific signatures for small-molecule p53 activators . Cell Cycle . 10 . 10 . 1590–1598 . May 2011 . 21490429 . 10.4161/cc.10.10.15519 . Landes Bioscience . free .
5. Davis TA, Johnston JN . 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 . 22708054 . 3375951 . 10.1039/C1SC00061F .
6. Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, Holak TA . Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells . Cancers . 10 . 11 . 396 . October 2018 . 30352966 . 6266412 . 10.3390/cancers10110396 . free .
7. Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Sosonyuk SE, Kopeina GS, Lozinskaya NA. December 2021. Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors . Medicinal Chemistry Research. en. 30. 12. 2216–2227. 10.1007/s00044-021-02802-w. 241788123 . 1054-2523.
8. Bazanov DR, Pervushin NV, Savitskaya VY, Anikina LV, Proskurnina MV, Lozinskaya NA, Kopeina GS . 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 . 31196710 . 10.1016/j.bmcl.2019.06.007 . 189815065 .
9. Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Savitskaya VY, Sosonyuk SE, Gracheva YA, Seliverstov MY, Lozinskaya NA, Kopeina GS . Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core . Pharmaceuticals . 15 . 4 . 444 . April 2022 . 35455441 . 9027661 . 10.3390/ph15040444 . free .