DOI: 10.1073/pnas.0708917105. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition

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

10.1073/pnas.0708917105

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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 animals. MI-219 warrants clinical investigation as a new agent for cancer treatment.

Bibliography

Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., Bernard, D., Zhang, J., Lu, Y., Gu, Q., Shah, R. B., Pienta, K. J., Ling, X., Kang, S., Guo, M., â¦ Wang, S. (2008). Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proceedings of the National Academy of Sciences, 105(10), 3933â3938.

Authors 22

Sanjeev Shangary (first)
Dongguang Qin (additional)
Donna McEachern (additional)
Meilan Liu (additional)
Rebecca S. Miller (additional)
Su Qiu (additional)
Zaneta Nikolovska-Coleska (additional)
Ke Ding (additional)
Guoping Wang (additional)
Jianyong Chen (additional)
Denzil Bernard (additional)
Jian Zhang (additional)
Yipin Lu (additional)
Qingyang Gu (additional)
Rajal B. Shah (additional)
Kenneth J. Pienta (additional)
Xiaolan Ling (additional)
Sanmao Kang (additional)
Ming Guo (additional)
Yi Sun (additional)
Dajun Yang (additional)
Shaomeng Wang (additional)

References 42 Referenced 567

10.1016/S0092-8674(00)81871-1
10.1038/35042675
10.1038/nrc864
10.1038/sj.onc.1207116
10.1016/S0065-230X(08)60785-X
10.1038/nrc991
10.1126/science.1092472
10.1016/j.molmed.2006.11.002
10.1038/sj.cdd.4401921
10.1038/nature05529
10.1038/nature05541
10.1016/j.cell.2006.12.007
10.1038/nature05567
10.1016/j.cell.2007.02.022
10.1016/j.critrevonc.2004.07.002
10.1007/s000180050273
10.1006/geno.1993.1058
10.4161/cc.3.4.801
10.1073/pnas.0507493103
10.1158/0008-5472.CAN-07-0200
10.1074/jbc.C600147200
10.1158/1535-7163.MCT-04-0342
10.1182/blood-2005-02-0553
10.1016/j.ccr.2006.10.010
10.1126/science.274.5289.948
10.1021/ja051147z
10.1021/jm051122a
10.1002/j.1460-2075.1996.tb00919.x
10.1038/sj.onc.1202281
10.1038/nature05194
10.1006/scbi.1998.0097
10.1016/j.critrevonc.2005.10.005
CG Maki, JM Huibregtse, PM Howley Cancer Res 56, 2649–2654 (1996). / Cancer Res by Maki CG (1996)
WS el-Deiry, JW Harper, PM O'Connor, VE Velculescu, CE Canman, J Jackman, JA Pietenpol, M Burrell, DE Hill, Y Wang, et al. Cancer Res 54, 1169–1174 (1994). / Cancer Res by el-Deiry WS (1994)
10.1016/S1097-2765(00)80002-7
10.1158/0008-5472.CAN-05-3832
10.1038/362847a0
10.1002/stem.150082
10.1002/1097-0142(196810)22:4<767::AID-CNCR2820220412>3.0.CO;2-7
10.1128/MCB.23.2.462-473.2003
10.1126/science.1068999
10.1182/blood-2007-09-112698

Dates

Type	When
Created	17 years, 5 months ago (March 3, 2008, 8:54 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 5:02 p.m.)
Indexed	1 month, 1 week ago (July 22, 2025, 6:56 a.m.)
Issued	17 years, 5 months ago (March 11, 2008)
Published	17 years, 5 months ago (March 11, 2008)
Published Online	17 years, 5 months ago (March 11, 2008)
Published Print	17 years, 5 months ago (March 11, 2008)

Funders 0

None

BibTeX

@article{Shangary_2008, title={Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition}, volume={105}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0708917105}, DOI={10.1073/pnas.0708917105}, number={10}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Shangary, Sanjeev and Qin, Dongguang and McEachern, Donna and Liu, Meilan and Miller, Rebecca S. and Qiu, Su and Nikolovska-Coleska, Zaneta and Ding, Ke and Wang, Guoping and Chen, Jianyong and Bernard, Denzil and Zhang, Jian and Lu, Yipin and Gu, Qingyang and Shah, Rajal B. and Pienta, Kenneth J. and Ling, Xiaolan and Kang, Sanmao and Guo, Ming and Sun, Yi and Yang, Dajun and Wang, Shaomeng}, year={2008}, month=mar, pages={3933–3938} }

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