Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling

Swati Kushal, Brooke Bullock Lao, Laura K. Henchey, Ramin Dubey, Hanah Mesallati, Nathaniel J. Traaseth, Bogdan Z. Olenyuk, Paramjit S. Arora

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)15602-15607
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number39
DOIs
StatePublished - Sep 24 2013

Keywords

  • Helix mimetics
  • Hydrogen bond surrogate helices
  • Rational design
  • Synthetic inhibitors of transcription

ASJC Scopus subject areas

  • General

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