REL-4-[[(4R,5S)-4,5-双(4-氯苯基)-4,5-二氢-2-[4-甲氧基-2-(1-甲基乙氧基)苯基]-1H-咪唑-1-基]羰基]-2-哌嗪酮

Ki: 90 nM (p53-MDM2)

Nutlin-3 is an inhibitor of the MDM2-p53 interaction. In particular, co-treatment of p53-positive HCT116 cells with 1 μM of Inauhzin and 2 μM of Nutlin-3 more significantly activated p53 as measured by its protein level as well as the level of its target p21, PUMA or cleaved PARP as indication of apoptosis. Nutlin-3 is a small-molecule inhibitor that acts to inhibit MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. As a single agent, Nutlin-3 (2-10 μM) stabilizes p53 and p21 ^WAF levels and is toxic to WTp53-22RV1 cells (IC ₅₀ , 4.3 μM) but has minimal toxicity toward p53-deficient cells (IC ₅₀ , >10 μM). Nutlin-3 induces p53 and p21 ^WAF expression in a dose-dependent manner in 22RV1 cells. Short-term cell cycle assays show that, at a dose of 10 μM, Nutlin-3 increasea slightly the G ₁ -phase fraction and decreasea S-phase fraction of all three cell lines.

Nutlin-3 can suppress the growth of xenograft tumors derived from human osteosarcoma or leukemia cells, the anti-tumor activity of Nutlin-3 even at the dose of 200 mg/kg per oral administration is marginal in an HCT116-derived xenograft tumor model. Nutlin-3 may be a useful adjunct to improve the therapeutic ratio using precision radiotherapy targeted to hypoxic cells and warrants further study in vivo.