title: A spiroligomer α-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture.
abstract: 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.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Zachary Z
authors.initials: ZZ
authors.lastname: Brown
authors.forename: Kavitha
authors.initials: K
authors.lastname: Akula
authors.forename: Alla
authors.initials: A
authors.lastname: Arzumanyan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alleva
authors.forename: Marcus
authors.initials: M
authors.lastname: Jackson
authors.forename: Eugeney
authors.initials: E
authors.lastname: Bichenkov
authors.forename: Joel B
authors.initials: JB
authors.lastname: Sheffield
authors.forename: Mark A
authors.initials: MA
authors.lastname: Feitelson
authors.forename: Christian E
authors.initials: CE
authors.lastname: Schafmeister
mesh_terms: D001665:Binding Sites; D001692:Biological Transport; D045744:Cell Line, Tumor; D004058:Diffusion; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060327:Solid-Phase Synthesis Techniques; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2