The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide
Open accessAbstract
The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum, and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions.
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Cites
Regulation of p53 stability by Mdm2
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Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
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Cytoplasmic functions of the tumour suppressor p53
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Disruption of p53 in human cancer cells alters the responses to therapeutic agents.
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Awakening guardian angels: drugging the p53 pathway
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MDMX: a novel p53‐binding protein with some functional properties of MDM2.
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Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
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Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
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Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2
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Cited by
Drugging the p53 pathway: understanding the route to clinical efficacy
Khoo, K. H., Verma, C. S., & Lane, D. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4236 · Cited by 719
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497
New Modalities for Challenging Targets in Drug Discovery
Valeur, E., Guéret, S. M., Adihou, H., Gopalakrishnan, R., Lemurell, M., Waldmann, H., Grossmann, T. N., & Plowright, A. T. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201611914 · Cited by 382
RNA Display Methods for the Discovery of Bioactive Macrocycles
Huang, Y., Wiedmann, M. M., & Suga, H. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00430 · Cited by 298
Modulating protein–protein interactions: the potential of peptides
Nevola, L., & Giralt, E. (2015) · Chemical Communications · doi:10.1039/c4cc08565e · Cited by 289
Metadata
- Authors
- Ji, Y., Majumder, S., Millard, M., Borra, R., Bi, T., Elnagar, A. Y., Neamati, N., Shekhtman, A., & Camarero, J. A.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-07-25
- Volume
- 135
- Issue
- 31
- Pages
- 11623-11633
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2142623863
- Cited by
- 233
- References
- 9
- FWCI
- 13.28
- Type
- journal article
- Language
- en
- Open access
- green
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