Nutlin

Last updated

Nutlin 3
Nutlin 3 Structure.svg
Names
IUPAC name
(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one
Other names
Nutlin
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
EC Number
  • 637-233-8
PubChem CID
UNII
  • InChI=1S/C30H30Cl2N4O4/c1-18(2)40-25-16-23(39-3)12-13-24(25)29-34-27(19-4-8-21(31)9-5-19)28(20-6-10-22(32)11-7-20)36(29)30(38)35-15-14-33-26(37)17-35/h4-13,16,18,27-28H,14-15,17H2,1-3H3,(H,33,37)/t27-,28+/m1/s1
    Key: BDUHCSBCVGXTJM-IZLXSDGUSA-N
  • CC(C)OC1=C(C=CC(=C1)OC)C2=NC(C(N2C(=O)N3CCNC(=O)C3)C4=CC=C(C=C4)Cl)C5=CC=C(C=C5)Cl
Properties
C30H30Cl2N4O4
Molar mass 581.49 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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]

References

  1. ↑ Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. (February 2004). "In vivo activation of the p53 pathway by small-molecule antagonists of MDM2". Science. 303 (5659): 844–848. Bibcode:2004Sci...303..844V. doi:10.1126/science.1092472. PMID   14704432. S2CID   16132757.
  2. ↑ Shangary S, Wang S (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. 49: 223–241. doi:10.1146/annurev.pharmtox.48.113006.094723. PMC   2676449 . PMID   18834305.
  3. 1 2 Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, et al. (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. 103 (6): 1888–1893. doi: 10.1073/pnas.0507493103 . PMC   1413632 . PMID   16443686.
  4. ↑ van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, et al. (May 2011). "Mechanism-specific signatures for small-molecule p53 activators". Cell Cycle. 10 (10). Landes Bioscience: 1590–1598. doi: 10.4161/cc.10.10.15519 . PMID   21490429.
  5. ↑ Davis TA, Johnston JN (January 2011). "Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor". Chemical Science. 2 (6): 1076–1079. doi:10.1039/C1SC00061F. PMC   3375951 . PMID   22708054.
  6. ↑ Liu Y, Su Z, Tavana O, Gu W (10 June 2024). "Understanding the complexity of p53 in a new era of tumor suppression". Cancer Cell. 42 (6): 946–967. doi:10.1016/j.ccell.2024.04.009. ISSN   1535-6108. PMC   11190820 . PMID   38729160.
  7. ↑ Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, et al. (October 2018). "Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells". Cancers. 10 (11): 396. doi: 10.3390/cancers10110396 . PMC   6266412 . PMID   30352966.
  8. ↑ Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Sosonyuk SE, et al. (December 2021). "Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors". Medicinal Chemistry Research. 30 (12): 2216–2227. doi:10.1007/s00044-021-02802-w. ISSN   1054-2523. S2CID   241788123.
  9. ↑ Bazanov DR, Pervushin NV, Savitskaya VY, Anikina LV, Proskurnina MV, Lozinskaya NA, et al. (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. 29 (16): 2364–2368. doi:10.1016/j.bmcl.2019.06.007. PMID   31196710. S2CID   189815065.
  10. ↑ Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Savitskaya VY, et al. (April 2022). "Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core". Pharmaceuticals. 15 (4): 444. doi: 10.3390/ph15040444 . PMC   9027661 . PMID   35455441.
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