Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (10), p.3933-3938
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological Sciences; Cancer; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell lines; Cell Proliferation - drug effects; Cells; Chemotherapy; Drug interactions; Heterologous transplantation; Humans; Indoles - administration & dosage; Indoles - blood; Indoles - chemistry; Indoles - pharmacology; Laboratory staining techniques; Mice; Models, Molecular; Molecules; Neoplasms - pathology; Protein Binding - drug effects; Proteins; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Spiro Compounds - administration & dosage; Spiro Compounds - blood; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Time Factors; Tumor Suppressor Protein p53 - metabolism; Tumors; Up regulation; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0708917105

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 Ki 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.