2012/10/18 by Zachary Z. Brown, Kavitha Akula, Alla Arzumanyan +6 · 2 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Cancer-related Molecular Pathways #Epigenetics and DNA Methylation #Cancer-related gene regulation
paper · pdf · doi:10.1371/journal.pone.0045948
openalex publication_date 2012/10/18 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/03
We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop.