Shangary Sanjeev, Qin Dongguang, McEachern Donna, Liu Meilan, Miller Rebecca S, Qiu Su, Nikolovska-Coleska Zaneta, Ding Ke, Wang Guoping, Chen Jianyong, Bernard Denzil, Zhang Jian, Lu Yipin, Gu Qingyang, Shah Rajal B, Pienta Kenneth J, Ling Xiaolan, Kang Sanmao, Guo Ming, Sun Yi, Yang Dajun, Wang Shaomeng
Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3933-8. doi: 10.1073/pnas.0708917105. Epub 2008 Mar 3.
We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2-p53 interaction. MI-219 binds to human MDM2 with a K(i) value of 5 nM and is 10,000-fold selective for MDM2 over MDMX. It disrupts the MDM2-p53 interaction and activates the p53 pathway in cells with wild-type p53, which leads to induction of cell cycle arrest in all cells and selective apoptosis in tumor cells. MI-219 stimulates rapid but transient p53 activation in established tumor xenograft tissues, resulting in inhibition of cell proliferation, induction of apoptosis, and complete tumor growth inhibition. MI-219 activates p53 in normal tissues with minimal p53 accumulation and is not toxic to animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.
我们已将MI-219设计为一种强效、高选择性且口服活性的小分子MDM2-p53相互作用抑制剂。MI-219与人MDM2结合，解离常数（K(i)）值为5 nM，对MDM2的选择性比对MDMX高10000倍。它破坏MDM2-p53相互作用，并在具有野生型p53的细胞中激活p53途径，这导致所有细胞的细胞周期停滞以及肿瘤细胞的选择性凋亡。MI-219在已建立的肿瘤异种移植组织中刺激p53快速但短暂的激活，从而抑制细胞增殖、诱导凋亡并完全抑制肿瘤生长。MI-219在正常组织中激活p53，p53积累极少，且对动物无毒。MI-219作为一种新型癌症治疗药物值得进行临床研究。
