{{Use dmy dates|date=February 2022}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Chembox | Verifiedfields = changed | Watchedfields = changed | Name = Nutlin 3 | verifiedrevid = 433813167 | ImageFile = Nutlin 3 Structure.svg | ImageSize = | IUPACName = (±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one | OtherNames = Nutlin |Section1={{Chembox Identifiers | CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 548472-68-0 | ChEBI = 46742 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 191334 | ChemSpiderID = 187530 | DrugBank = DB17039 | EC_number = 637-233-8 | PubChem = 16755649 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 53IA0V845C | StdInChI=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 | StdInChIKey = BDUHCSBCVGXTJM-IZLXSDGUSA-N | SMILES = 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 }} |Section2={{Chembox Properties | C=30|H=30|Cl=2|N=4|O=4 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}
'''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),<ref name="Nutlin">{{cite journal | vauthors = Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA | title = In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 | journal = Science | volume = 303 | issue = 5659 | pages = 844–848 | date = February 2004 | pmid = 14704432 | doi = 10.1126/science.1092472 | s2cid = 16132757 | bibcode = 2004Sci...303..844V }}</ref> but nutlin-3 is most commonly used in anti-cancer studies.<ref name="annrev">{{cite journal | vauthors = Shangary S, Wang S | title = Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy | journal = Annual Review of Pharmacology and Toxicology | volume = 49 | pages = 223–241 | year = 2008 | pmid = 18834305 | pmc = 2676449 | doi = 10.1146/annurev.pharmtox.48.113006.094723 }}</ref> Nutlins disrupt the p53–MDM2 interaction by occupying a p53-binding pocket of MDM2.<ref name=":0">{{cite journal | vauthors = 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 | title = Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 6 | pages = 1888–1893 | date = February 2006 | pmid = 16443686 | pmc = 1413632 | doi = 10.1073/pnas.0507493103 | doi-access = free }}</ref> Many tumors that express normal p53 and normal or elevated levels of MDM2 may be targeted using nutlin.<ref name=":0" /> Nutlin-3 acts quickly in vitro, leading to increased levels of p53 protein within minutes.<ref name="Leeuwen et al.">{{cite journal | vauthors = van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, Pirrie L, Westwood NJ, Laín S | title = Mechanism-specific signatures for small-molecule p53 activators | journal = Cell Cycle | volume = 10 | issue = 10 | pages = 1590–1598 | date = May 2011 | pmid = 21490429 | doi = 10.4161/cc.10.10.15519 | publisher = Landes Bioscience | doi-access = free }}</ref>
The more potent of the two enantiomers, nutlin-3a ((–)-nutlin-3), can be synthesized in a highly enantioselective fashion.<ref>{{cite journal | vauthors = Davis TA, Johnston JN | title = Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor | journal = Chemical Science | volume = 2 | issue = 6 | pages = 1076–1079 | date = January 2011 | pmid = 22708054 | pmc = 3375951 | doi = 10.1039/C1SC00061F }}</ref> 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.<ref>{{Cite journal |last=Liu |first=Yanqing |last2=Su |first2=Zhenyi |last3=Tavana |first3=Omid |last4=Gu |first4=Wei |date=2024-06-10 |title=Understanding the complexity of p53 in a new era of tumor suppression |url=https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00133-8 |journal=Cancer Cell |language=English |volume=42 |issue=6 |pages=946–967 |doi=10.1016/j.ccell.2024.04.009 |issn=1535-6108 |pmc=11190820 |pmid=38729160}}</ref><ref>{{cite journal | vauthors = Skalniak L, Kocik J, Polak J, Skalniak A, Rak M, Wolnicka-Glubisz A, Holak TA | title = Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells | journal = Cancers | volume = 10 | issue = 11 | page = 396 | date = October 2018 | pmid = 30352966 | pmc = 6266412 | doi = 10.3390/cancers10110396 | doi-access = free }}</ref> Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.<ref>{{Cite journal| vauthors = Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Sosonyuk SE, Kopeina GS, Lozinskaya NA|date=December 2021|title=Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors |journal=Medicinal Chemistry Research|language=en|volume=30|issue=12|pages=2216–2227|doi=10.1007/s00044-021-02802-w|s2cid=241788123 |issn=1054-2523}}</ref><ref>{{cite journal | vauthors = Bazanov DR, Pervushin NV, Savitskaya VY, Anikina LV, Proskurnina MV, Lozinskaya NA, Kopeina GS | title = 2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation | journal = Bioorganic & Medicinal Chemistry Letters | volume = 29 | issue = 16 | pages = 2364–2368 | date = August 2019 | pmid = 31196710 | doi = 10.1016/j.bmcl.2019.06.007 | s2cid = 189815065 }}</ref><ref>{{cite journal | vauthors = Bazanov DR, Pervushin NV, Savin EV, Tsymliakov MD, Maksutova AI, Savitskaya VY, Sosonyuk SE, Gracheva YA, Seliverstov MY, Lozinskaya NA, Kopeina GS | title = Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core | journal = Pharmaceuticals | volume = 15 | issue = 4 | pages = 444 | date = April 2022 | pmid = 35455441 | pmc = 9027661 | doi = 10.3390/ph15040444 | doi-access = free }}</ref> 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. <ref>{{cite journal | vauthors = Bazanov DR, Lozinskaya NA | title = The evolution of Nutlins as p53-MDM2 inhibitors | journal = Medicinal Chemistry Research | doi = 10.1007/s00044-025-03492-4 }}</ref>
== References == {{Reflist}}
Category:Imidazolines Category:4-Chlorophenyl compounds Category:Isopropyl compounds Category:Piperazinones Category:Methoxy compounds Category:Ureas