Inhibiting S100B(ββ) for Activating Wild-Type p53: Design of Stapled Peptides

S100B(ββ) is a member of the S100B protein family and is distributed in a cell-specific manner. Its levels are elevated in several cancers such as malignant melanoma and correlate directly with poor prognosis in patients. S100B(ββ) directly interacts with the tumor suppressor p53, inhibiting tetramerization and protein kinase C-dependent phosphorylation, consequently decreasing p53 DNA binding and transcriptional activity, and preventing apoptosis. Thus, S100B(ββ) is being pursued as a target for therapeutic inhibition. However, development of small molecule inhibitors targeting p53-interactions has met with limited success. In this work, we present a set of designed stapled peptide inhibitors of S100B(ββ), guided by the structure of the C-terminal domain of p53 complexed with S100B(ββ). We further modified a tightly binding stapled peptide with imaging agents and propose these as potential diagnostic agents to detect S100B(ββ) as a biomarker. NRF (Natl Research Foundation, S’pore) ASTAR (Agency for Sci., Tech. and Research, S’pore) EDB (Economic Devt. Board, S’pore) Published version