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

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International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

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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Acknowledgments

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).

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Authors and Affiliations

  1. Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA, 90095, USA

    Ewa D. Micewicz & William H. McBride

  2. Materials and Process Simulation Center, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA, 91125, USA

    Shantanu Sharma

  3. Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA, 90502, USA

    Alan J. Waring

  4. Department of Analytical Operations, Gilead Sciences, Inc., 4049 Avenida de la Plata, Oceanside, CA, 92056, USA

    Hai T. Luong

  5. Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA, 90024, USA

    Piotr Ruchala

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  1. Ewa D. Micewicz
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Correspondence to Piotr Ruchala.

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Micewicz, E.D., Sharma, S., Waring, A.J. et al. Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation. Int J Pept Res Ther 22, 67–81 (2016). https://doi.org/10.1007/s10989-015-9487-3

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