Nutlin-3a

Описание

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.

Определение

ChEBI: Nutlin-3 is a stilbenoid. It is a small molecule inhibitor that targets p53-Mdm2 interaction.

Биохимия/физиол Действия

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

Способ действия

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

использованная литература

[1] LYUBOMIR T. VASSILEV. In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2[J]. Science, 2004, 303 5659. DOI:10.1126/science.1092472.
[2] YOKO TABE. MDM2 antagonist nutlin-3 displays antiproliferative and proapoptotic activity in mantle cell lymphoma.[J]. Clinical Cancer Research, 2009, 15 3: 933-942. DOI:10.1158/1078-0432.CCR-08-0399.
[3] SHINJI ENDO. Potent in vitro and in vivo antitumor effects of MDM2 inhibitor nutlin-3 in gastric cancer cells[J]. Cancer Science, 2010, 102 3: 605-613. DOI:10.1111/j.1349-7006.2010.01821.x.
[4] HONG SHEN  Carl G M. Pharmacologic activation of p53 by small-molecule MDM2 antagonists.[J]. Current pharmaceutical design, 2011, 17 6: 560-568. DOI:10.2174/138161211795222603.