Regulating the ARNT/TACC3 axis: Multiple approaches to manipulating protein/protein interactions with small molecules

Yirui Guo, Carrie L. Partch, Jason Key, Paul B. Card, Victor Pashkov, Anjana Patel, Richard K. Bruick, Heiko Wurdak, Kevin H. Gardner

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

For several well-documented reasons, it has been challenging to develop artificial small molecule inhibitors of protein/protein complexes. Such reagents are of particular interest for transcription factor complexes given links between their misregulation and disease. Here we report parallel approaches to identify regulators of a hypoxia signaling transcription factor complex, involving the ARNT subunit of the HIF (Hypoxia Inducible Factor) activator and the TACC3 (Transforming Acidic Coiled Coil Containing Protein 3) coactivator. In one route, we used in vitro NMR and biochemical screening to identify small molecules that selectively bind within the ARNT PAS (Per-ARNT-Sim) domain that recruits TACC3, identifying KG-548 as an ARNT/TACC3 disruptor. A parallel, cell-based screening approach previously implicated the small molecule KHS101 as an inhibitor of TACC3 signaling. Here, we show that KHS101 works indirectly on HIF complex formation by destabilizing both TACC3 and the HIF component HIF-1α. Overall, our data identify small molecule regulators for this important complex and highlight the utility of pursuing parallel strategies to develop protein/protein inhibitors.

Original languageEnglish (US)
Pages (from-to)626-635
Number of pages10
JournalACS Chemical Biology
Volume8
Issue number3
DOIs
StatePublished - Mar 15 2013

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Molecules
Proteins
Screening
Transcription Factors
Hypoxia-Inducible Factor 1
Nuclear magnetic resonance
Hypoxia
KHS101

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Medicine(all)

Cite this

Regulating the ARNT/TACC3 axis : Multiple approaches to manipulating protein/protein interactions with small molecules. / Guo, Yirui; Partch, Carrie L.; Key, Jason; Card, Paul B.; Pashkov, Victor; Patel, Anjana; Bruick, Richard K.; Wurdak, Heiko; Gardner, Kevin H.

In: ACS Chemical Biology, Vol. 8, No. 3, 15.03.2013, p. 626-635.

Research output: Contribution to journalArticle

Guo, Yirui ; Partch, Carrie L. ; Key, Jason ; Card, Paul B. ; Pashkov, Victor ; Patel, Anjana ; Bruick, Richard K. ; Wurdak, Heiko ; Gardner, Kevin H. / Regulating the ARNT/TACC3 axis : Multiple approaches to manipulating protein/protein interactions with small molecules. In: ACS Chemical Biology. 2013 ; Vol. 8, No. 3. pp. 626-635.
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