Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition
University of Michigan · Comprehensive Blood & Cancer Center
Abstract
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…
Citation impact
- FWCI
- 25.15
- Percentile
- 100%
- References
- 42
Authors
22- SSSanjeev ShangaryCorresponding
University of Michigan, Comprehensive Blood & Cancer Center
- DQDongguang Qin
University of Michigan, Comprehensive Blood & Cancer Center
- DMDonna McEachern
University of Michigan, Comprehensive Blood & Cancer Center
- MLMeilan Liu
University of Michigan, Comprehensive Blood & Cancer Center
- RSRebecca S. Miller
University of Michigan, Comprehensive Blood & Cancer Center
Topics & keywords
- MDMX
- Mdm2
- Apoptosis
- Growth inhibition
- Cancer research
- Cell cycle checkpoint
- Cell growth
- Cell cycle
- Good health and well-being