675576-98-4

Nutlin-3 is a novel small-molecule antagonist of the human homolog of mouse double minute (MDM2) that binds MDM2 in the p53-binding pocket and activates the p53 signaling pathway.

(ndash)-Nutlin-3 is an inhibitor of p-53-MDM2 interaction. Anti-cancer agent.

ChEBI: 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazol-1-yl]-oxomethyl]-2-piperazinone is a stilbenoid.

nutlin-3 is a small-molecule inhibitor of mdm2 (mouse double minute 2) with ic50 value of 0.09μm [1].nutlin-3 binds mdm2 in the tp53-bindingpocket, thereby interfering with mdm2-directed tp53 degradation. this has been shown to cause cell cycle arrest, growth inhibitionand apoptosis in both solid tumors and lymphoid neoplasms.in mantle cell lymphoma(mcl), it is reported that nutlin-3 can inhibit cell growth and activate apoptosis in bothwt-tp53(ic50 of 1 to 10μm) and mt-tp53(ic50 of 22.5μm) cells [2].nutlin-3 can also effectcell cycle in gastric cancer cell lines. it induces g1 arrest inmkn-45 and snu-1 cell lines. in vitro assay shows nutlin-3can enhance the antitumoreffects of conventional chemotherapeutic agents in several gastric cancer cell lines. and in in vivo assay, nutlin-3 significantly inhibits the growth of xenograft tumors [3].

Nutlin-3a is a potent nongenotoxic drug. It acts as a tumor suppressor p53 (TP53) activator and stabilizer.

MDM2

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Nutlin-3 binds to the p53 binding pocket in MDM2 and inhibits the p53/MDM2 interaction, leading to stabilization of p53 and induction of p53-dependent cell cycle arrest or apoptosis. Nutlin-3 can also inhibit cancer cell migration and invasion in a p53-dependent manner, most likely through inhibition of RhoA and Rac1 activity. In addition to p53, Nutlin-3 also blocks the interaction of MDM2 with p73, E2F1, HIF-1α, resulting in increased apoptosis (p73, E2F1) and decreased VEGF production and decreased angiogenesis (HIF-1α). Nutlin-3 is predicted to block the interaction of MDM2 and Numb.

Molecular Mechanisms of the actions of Nutlin-3

[1] lyubomir t.vassilev et al. in vivo activation of the p53 pathway by small-molecule antagonists of mdm2.science.2004, 303: 844-848.
[2] yoko tabe, denise sebasigari, linhua jin, et al.mdm2 antagonist nutlin-3 displays antiproliferative andproapoptotic activity in mantle cell lymphoma. clin cancer res. 2009, 15:933-942.
[3] shinji endo,kenji yamato,sachiko hirai,toshikazu moriwaki,kuniaki fukuda,hideo suzuki,masato abei,ichiro nakagawa and ichinosukehyodo.potent in vitro and in vivo antitumor effects ofmdm2 inhibitor nutlin-3 in gastric cancer cells.cancer science. 2011, 102 (3): 605-613.