Nutlins are a family of small molecule, ''cis''-

imidazoline Imidazoline is a heterocycle formally derived from imidazole by the reduction of one of the two double bonds. Three isomers are known, 2-imidazolines, 3-imidazolines, and 4-imidazolines. The 2- and 3-imidazolines contain an imine center, whereas t ...

analogs, which inhibit the interaction between MDM2 and tumor suppressor

p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

, 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

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s, 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.

References

{{Reflist Imidazolines 4-Chlorophenyl compounds Isopropyl compounds Piperazinones Methoxy compounds Ureas