Nutlins are ''cis''-
imidazoline
Imidazoline is a class of heterocycles formally derived from imidazoles 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
In ...
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 protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, 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;
however, Nutlin-3 is the compound most commonly used in anti-cancer studies.
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. Inhibiting the interaction between mdm2 and p53 stabilizes p53, and is thought to selectively induce a growth-inhibiting state called
senescence
Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
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.
The more potent of the two
enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
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. Imidazoline core based on the methoxyphenyl substituents also stabilizes p53.
References
Imidazolines
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