title: Novel pyrrolopyrimidine-based α-helix mimetics: cell-permeable inhibitors of protein−protein interactions.
abstract: There is considerable interest in developing non-peptidic, small-molecule α-helix mimetics to disrupt α-helix-mediated protein−protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid-phase synthetic route that is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell-permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics.
authors.affiliation: Department of Biochemistry and Molecular Biology, and Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sunhwan
authors.initials: S
authors.lastname: Jo
authors.forename: Sergio C
authors.initials: SC
authors.lastname: Chai
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Lim
mesh_terms: D000595:Amino Acid Sequence; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D010539:Permeability; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; C527741:pyrrolopyrimidine; D051736:Proto-Oncogene Proteins c-mdm2