title: In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics.
abstract: Development of small-molecule inhibitors of protein-protein interactions is a fundamental challenge at the interface of chemistry and cancer biology. Successful methods for design of protein-protein interaction inhibitors include computational and experimental high-throughput and fragment-based screening strategies to locate small-molecule fragments that bind protein surfaces. An alternative rational design approach seeks to mimic the orientation and disposition of critical binding residues at protein interfaces. We describe the design, synthesis, biochemical, and in vivo evaluation of a small-molecule scaffold that captures the topography of α-helices. We designed mimics of a key α-helical domain at the interface of hypoxia-inducible factor 1α and p300 to develop inhibitors of hypoxia-inducible signaling. The hypoxia-inducible factor/p300 interaction regulates the transcription of key genes, whose expression contributes to angiogenesis, metastasis, and altered energy metabolism in cancer. The designed compounds target the desired protein with high affinity and in a predetermined manner, with the optimal ligand providing effective reduction of tumor burden in experimental animal models.
authors.affiliation: Department of Chemistry, New York University, New York, NY 10003; and.
authors.forename: Brooke Bullock
authors.initials: BB
authors.lastname: Lao
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089.
authors.forename: Ivan
authors.initials: I
authors.lastname: Grishagin
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089.
authors.forename: Hanah
authors.initials: H
authors.lastname: Mesallati
authors.affiliation: Department of Chemistry, New York University, New York, NY 10003; and.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Brewer
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089 arora@nyu.edu bogdan@usc.edu.
authors.forename: Bogdan Z
authors.initials: BZ
authors.lastname: Olenyuk
authors.affiliation: Department of Chemistry, New York University, New York, NY 10003; and arora@nyu.edu bogdan@usc.edu.
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Arora
mesh_terms: D000595:Amino Acid Sequence; D000693:Anaerobiosis; D000818:Animals; D032701:Biomimetics / Q000379:methods*; D015153:Blotting, Western; D003001:Cloning, Molecular; D055808:Drug Discovery / Q000379:methods*; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016296:Mutagenesis; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010879:Piperazines; D054852:Small Molecule Libraries; D000077489:Piperazine; D008156:Luciferases; D050880:p300-CBP Transcription Factors
keywords: helix mimics; hypoxia signaling; synthetic inhibitors of transcription