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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3933-3938
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number10
DOIs
StatePublished - Mar 25 2008
Externally publishedYes

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Poisons
Growth
Neoplasms
Apoptosis
Cell Cycle Checkpoints
Heterografts
Cell Proliferation
MI-219

Keywords

  • Cancer therapy
  • MDM2-p53 protein-protein interaction
  • Selective toxicity to tumors
  • Small-molecule inhibitor

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 10, 25.03.2008, p. 3933-3938.

Research output: Contribution to journalArticle

Shangary, S, Qin, D, McEachern, D, Liu, M, Miller, RS, Qiu, S, Nikolovska-Coleska, Z, Ding, K, Wang, G, Chen, J, Bernard, D, Zhang, J, Lu, Y, Gu, Q, Shah, RB, Pienta, KJ, Ling, X, Kang, S, Guo, M, Sun, Y, Yang, D & 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 of the United States of America, vol. 105, no. 10, pp. 3933-3938. https://doi.org/10.1073/pnas.0708917105
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. / Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 10. pp. 3933-3938.
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AU - Miller, Rebecca S.

AU - Qiu, Su

AU - Nikolovska-Coleska, Zaneta

AU - Ding, Ke

AU - Wang, Guoping

AU - Chen, Jianyong

AU - Bernard, Denzil

AU - Zhang, Jian

AU - Lu, Yipin

AU - Gu, Qingyang

AU - Shah, Rajal B.

AU - Pienta, Kenneth J.

AU - Ling, Xiaolan

AU - Kang, Sanmao

AU - Guo, Ming

AU - Sun, Yi

AU - Yang, Dajun

AU - Wang, Shaomeng

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