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Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation

Micewicz, Ewa D. and Sharma, Shantanu and Waring, Alan J. and Luong, Hai T. and McBride, William H. and Ruchala, Piotr (2016) Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation. International Journal of Peptide Research and Therapeutics, 22 (1). pp. 67-81. ISSN 1573-3149. PMCID PMC4779441. doi:10.1007/s10989-015-9487-3.

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A small library of anticancer, cell-permeating, stapled peptides based on potent dual-specific antagonist of p53–MDM2/MDMX interactions, PMI-N8A, was synthesized, characterized and screened for anticancer activity against human colorectal cancer cell line, HCT-116. Employed synthetic modifications included: S-alkylation-based stapling, point mutations increasing hydrophobicity in key residues as well as improvement of cell-permeability by introduction of polycationic sequence(s) that were woven into the sequence of parental peptide. Selected analogue, ArB14Co, was also tested in vivo and exhibited potent anticancer bioactivity at the low dose (3.0 mg/kg). Collectively, our findings suggest that application of stapling in combination with rational design of polycationic short analogues may be a suitable approach in the development of physiologically active p53–MDM2/MDMX peptide inhibitors.

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Waring, Alan J.0000-0002-0151-2695
Additional Information:© 2016 Springer Netherlands. First online: 19 August 2015. This project was partially supported by funds from the Adams and Burnham endowments provided by the Dean’s Office of the David Geffen School of Medicine at UCLA (PR) and the NIH/NIAID award 5U19AI067769 (EDM and WHM). Authors declare that this article content has no conflict of interest. The article does not contain any studies in patients by any of the authors. This article does not contain studies involving human subjects. All animal experiments were approved by the UCLA Animal Care and Use Committee and conformed to local and national guidelines.
Subject Keywords:Antagonists of p53 – Anticancer agents – S-alkylation of peptides – Drug design – Cell permeable peptides
Issue or Number:1
PubMed Central ID:PMC4779441
Record Number:CaltechAUTHORS:20160602-123203607
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67574
Deposited By: Tony Diaz
Deposited On:02 Jun 2016 19:50
Last Modified:24 May 2022 22:32

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