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 Sun; Dajun Yang; Shaomeng Wang

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

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 journal › Article › peer-review

615 Scopus citations

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 language	English (US)
Pages (from-to)	3933-3938
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	105
Issue number	10
DOIs	https://doi.org/10.1073/pnas.0708917105
State	Published - Mar 25 2008
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General

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10.1073/pnas.0708917105

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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., ... 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, 105(10), 3933-3938. https://doi.org/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. / Shangary, Sanjeev; Qin, Dongguang; McEachern, Donna et al.
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 journal › Article › peer-review

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

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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 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.",

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AU - Shangary, Sanjeev

AU - Qin, Dongguang

AU - McEachern, Donna

AU - Liu, Meilan

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

PY - 2008/3/25

Y1 - 2008/3/25

N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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