title: Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation.
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 testedin vivoand 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.
authors.affiliation: Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Micewicz
authors.affiliation: Materials and Process Simulation Center, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA, Medical Center, 1000 West Carson Street, Torrance, CA 90502, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.affiliation: Department of Analytical Operations, Gilead Sciences, Inc., 4049 Avenida de la Plata, Oceanside CA, 92056, USA.
authors.forename: Hai T
authors.initials: HT
authors.lastname: Luong
authors.affiliation: Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
keywords: Antagonists of p53; Anticancer agents; Cell permeable peptides; Drug design; S-alkylation of peptides