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Article

The Dual Interactions of p53 with MDM2 and p300: Implications for the Design of MDM2 Inhibitors

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Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore
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MSD International, Translation Medicine Research Centre, Singapore 138665, Singapore
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p53 Laboratory, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore 138648, Singapore
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School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
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Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 5996; https://doi.org/10.3390/ijms20235996
Received: 24 October 2019 / Revised: 22 November 2019 / Accepted: 25 November 2019 / Published: 28 November 2019
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
Proteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide ALRN_6924 that activates p53 by preventing its interaction with its negative regulator Mdm2 has entered clinical trials. This stapled peptide mimics the interaction of p53 with Mdm2. The chances that this peptide could bind to other proteins that may also interact with the Mdm2-binding region of p53 are high; one such protein is the CREB binding protein (CBP)/p300. It has been established that phosphorylated p53 is released from Mdm2 and binds to p300, orchestrating the transcriptional program. We investigate whether molecules such as ALRN_6924 would bind to p300 and, to do so, we used molecular simulations to explore the binding of ATSP_7041, which is an analogue of ALRN_6924. Our study shows that ATSP_7041 preferentially binds to Mdm2 over p300; however, upon phosphorylation, it appears to have a higher affinity for p300. This could result in attenuation of the amount of free p300 available for interacting with p53, and hence reduce its transcriptional efficacy. Our study highlights the importance of assessing off-target effects of peptide inhibitors, particularly guided by the understanding of the networks of protein-protein interactions (PPIs) that are being targeted. View Full-Text
Keywords: stapled peptides; PPIs; MD simulations; phosphorylation; off-target effects stapled peptides; PPIs; MD simulations; phosphorylation; off-target effects
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MDPI and ACS Style

Kannan, S.; Partridge, A.W.; Lane, D.P.; Verma, C.S. The Dual Interactions of p53 with MDM2 and p300: Implications for the Design of MDM2 Inhibitors. Int. J. Mol. Sci. 2019, 20, 5996. https://doi.org/10.3390/ijms20235996

AMA Style

Kannan S, Partridge AW, Lane DP, Verma CS. The Dual Interactions of p53 with MDM2 and p300: Implications for the Design of MDM2 Inhibitors. International Journal of Molecular Sciences. 2019; 20(23):5996. https://doi.org/10.3390/ijms20235996

Chicago/Turabian Style

Kannan, Srinivasaraghavan, Anthony W. Partridge, David P. Lane, and Chandra S. Verma 2019. "The Dual Interactions of p53 with MDM2 and p300: Implications for the Design of MDM2 Inhibitors" International Journal of Molecular Sciences 20, no. 23: 5996. https://doi.org/10.3390/ijms20235996

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