title: Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling.
abstract: Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. Herein we report the design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor hypoxia-inducible factor-1α. Our results indicate that disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of nontargeted signaling pathways. We observed remarkable efficacy of the compound HBS 1 in suppressing tumor growth in the fully established murine xenograft models of renal cell carcinoma of the clear cell type. Our results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor-coactivator interfaces represent a unique approach for in vivo modulation of oncogenic signaling and arresting tumor growth.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089.
authors.forename: Swati
authors.initials: S
authors.lastname: Kushal
authors.forename: Brooke Bullock
authors.initials: BB
authors.lastname: Lao
authors.forename: Laura K
authors.initials: LK
authors.lastname: Henchey
authors.forename: Ramin
authors.initials: R
authors.lastname: Dubey
authors.forename: Hanah
authors.initials: H
authors.lastname: Mesallati
authors.forename: Nathaniel J
authors.initials: NJ
authors.lastname: Traaseth
authors.forename: Bogdan Z
authors.initials: BZ
authors.lastname: Olenyuk
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Arora
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D055550:Protein Stability / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051793:Hypoxia-Inducible Factor 1; D008024:Ligands; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D050880:p300-CBP Transcription Factors
keywords: helix mimetics; hydrogen bond surrogate helices; rational design; synthetic inhibitors of transcription
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