In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

Brooke Bullock Lao, Ivan Grishagin, Hanah Mesallati, Thomas F. Brewer, Bogdan Z. Olenyuk, Paramjit Arora

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7531-7536
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number21
DOIs
StatePublished - May 27 2014

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Proteins
Hypoxia-Inducible Factor 1
Tumor Burden
Energy Metabolism
Hypoxia
Neoplasms
Membrane Proteins
Animal Models
Neoplasm Metastasis
Ligands
Gene Expression

Keywords

  • Helix mimics
  • Hypoxia signaling
  • Synthetic inhibitors of transcription

ASJC Scopus subject areas

  • General

Cite this

In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics. / Lao, Brooke Bullock; Grishagin, Ivan; Mesallati, Hanah; Brewer, Thomas F.; Olenyuk, Bogdan Z.; Arora, Paramjit.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 21, 27.05.2014, p. 7531-7536.

Research output: Contribution to journalArticle

Lao, Brooke Bullock ; Grishagin, Ivan ; Mesallati, Hanah ; Brewer, Thomas F. ; Olenyuk, Bogdan Z. ; Arora, Paramjit. / In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 21. pp. 7531-7536.
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