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].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  HCT116 cells	-	Function assay	-	Inhibition of cell proliferation of human HCT116 cells expressing p53, IC50=0.454 μM	26181851
  PC3 cells	-	Function assay	-	Inhibition of mTORC2 in human PC3 cells assessed as inhibition of AKT phosphorylation at S473 after 1 hr, IC50=0.022 μM	26102506
  SJSA1 cells	-	Function assay	-	Inhibition of cell proliferation of human SJSA1 cells, GI50=0.35 μM	26181851

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01760525	Solid Tumor With p53 Wild Type... more >> Status Collapse <<	Phase 1	Active, not recruiting	January 9, 2019	United States, Massachusetts ... more >> Dana Farber Cancer Institute SC (2) Boston, Massachusetts, United States, 02215 France Novartis Investigative Site Lyon Cedex, France, 69373 Germany Novartis Investigative Site Koeln, Nordrhein-Westfalen, Germany, 50937 Novartis Investigative Site Essen, Germany, 45147 Singapore Novartis Investigative Site Singapore, Singapore, 169610 Switzerland Novartis Investigative Site Zürich, Switzerland, 8091 Collapse <<

• 参考文献

• [1] Reuther C, Heinzle V, et al. The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53 - p21 - Rb - E2F1 Cascade in the p53wildtype Neuroendocrine Tumor Cell Line GOT1. Neuroendocrinology. 2016 Nov 21.

  [2] Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

  [3] Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development