生物活性

• 描述Tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic protein that plays a central role in protectionfrom tumor development. The overproduction of MDM2, the primary negative regulator of p53, effectively disables p53 function^[3]. NVP-CGM097 is a potent and selective MDM2 antagonist which binds to human MDM2 (hMDM2) with an IC₅₀ value of 1.7 ± 0.1 nM. The selectivity of NVP-CGM097 to p53:MDM2 interaction was 1176 times that to p53:MDM4 interaction. Therefore, NVP-CGM097 is highly selective to p53:MDM2 interaction. NVP-CGM097 can significantly promote wild-type p53 to enter the cell nucleus with IC₅₀ value of 0.224 μM indicating that it can inhibit the interaction of p53:MDM2 interaction in living cells. After intravenous injection, the serum clearance rate of NVP-CGM097 was 5, 7, 3 and 4 mL/min/kg in mice, rats, dogs and monkeys, respectively. The half-life of NVP-CGM097 in rodents and monkeys is 6 - 12 hours. In dogs, the half-life is 20 hours. In MDM2-amplified SJSA1 human tumor model, NVP-CGM097 could inhibit the interaction between p53 and MDM2 and reactivate the p53 pathway. mRNA levels of p21 increased in tumor-bearing mice when given 30 mg/kg NVP-CGM097. Furthermore, daily administration of NVP-CGM097 to mice significantly inhibited the growth of SJSA1 tumors in a dose-dependent manner^[2].