Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2

Scheuermann, Thomas H.; Stroud, Daniel; Sleet, Christopher E.; Bayeh, Liela; Shokri, Cameron; Wang, Hanzhi; Caldwell, Charles G.; Longgood, Jamie; MacMillan, John B.; Bruick, Richard K.; Gardner, Kevin H.; Tambar, Uttam K.

doi:10.1021/acs.jmedchem.5b00529

Cited by 72 publications

(73 citation statements)

References 42 publications

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“…This model subsequently guided the authors to mutate surface amino-acid residues on each subunit (HIF-2α R247E and ARNT E362R), so as to create an artificial salt bridge that could further enhance the binding affinity of two PAS-B domains and facilitate their co-crystallization (Figure 1d) [15]. This artificial PAS-B heterodimer structure not only correlated with the original NMR-based model that two domains can form an interface via their β-sheets in an anti-parallel fashion, but more importantly revealed a large cavity (~300 Å 3 ) with the HIF-2α PAS-B domain [16–19]. …”

Section: Overall Structures Of Bhlh-pas Heterodimerssupporting

confidence: 58%

Structural characterization of mammalian bHLH-PAS transcription factors

Rastinejad

2017

Current Opinion in Structural Biology

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The mammalian basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factors share common architectural features that include a bHLH DNA-binding domain and tandemly positioned PAS domains. The sixteen members of this family include the hypoxia-inducible factors (HIF-1α and HIF-2α), ARNT (also known as HIF-1β), CLOCK and BMAL1. Most bHLH-PAS proteins have been genetically linked to variety of diseases in humans, including cancers, metabolic syndromes and psychiatric conditions. To function as transcription factors, the bHLH-PAS proteins must form heterodimeric complexes. Recent crystallographic studies of HIF-α-ARNT and CLOCK-BMAL1 complexes have unveiled the organization of their multi-domain bHLH-PAS-A-PAS-B segments, revealing how these architectures can give rise to unique patterns of heterodimerization. As our structural understanding becomes better integrated with ligand-discovery and target gene identification, a more comprehensive picture of their architectural and functional properties will emerge.

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Section: Overall Structures Of Bhlh-pas Heterodimerssupporting

confidence: 58%

Structural characterization of mammalian bHLH-PAS transcription factors

Rastinejad

2017

Current Opinion in Structural Biology

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“…In addition, conditioned media from esophageal cells that were treated with acidic bile salts were found to increase T cell migration rates in a transwell system. Finally, HIF-2α knockdown by shRNA and HIF-2α inhibition using a selective small molecule antagonist (S,R)-4 (Figure 2) [13] blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts [12]. [Note that (S,R)-4 was named (S,R)-37 Peak 2 in Reference 12] These observations support the hypothesis that reflux esophagitis develops through a cytokine-mediated process in which HIF-2α plays a central role (Figure 1).…”

Section: Hypoxia-inducible Factor-2α: a Key Mediator Of The Cytokine mentioning

confidence: 99%

“…Subsequent to this original study, Bruick, Gardner, MacMillan, and Tambar identified a more potent class of inhibitors of HIF-2α–HIF-β heterodimerization, which are based on a tetrazolo-tetrahydropyrimidine ring system ( 3 , Figure 2b) [13]. This general pharmacophore is preferred over compound 2 for several reasons.…”

Section: Isoform-selective Hif-2α Inhibitorsmentioning

confidence: 99%

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A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α: a potential role for targeting HIF-2α to prevent and treat reflux esophagitis

Souza

Bayeh

Spechler

et al. 2017

Current Opinion in Pharmacology

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Traditionally, reflux esophagitis was assumed to develop as a caustic, chemical injury inflicted by refluxed acid. Recently, however, studies in rats and humans suggest that reflux esophagitis develops as a cytokine-mediated inflammatory injury, with hypoxia inducible factor (HIF)-2α playing a major role. In response to the reflux of acid and bile, HIF-2α in esophageal epithelial cells becomes stabilized, thereby increasing production of pro-inflammatory cytokines that attract T lymphocytes and other inflammatory cells to damage the esophagus. Recent studies have identified small molecule inhibitors of HIF-2α that demonstrate exquisite isoform selectivity, and clinical trials for treatment of HIF-2α-driven kidney cancers are ongoing. It is conceivable that a HIF-2α-directed therapy might be a novel approach to prevention and treatment of reflux esophagitis.

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“…From 2003 an increasing structural knowledge on homologous proteins belonging to the bHLH-PAS family has become available and has greatly contributed to advancements in molecular understanding of the AhR structure and interactions [26–34]. In addition to well-conserved N-terminal domain structures, the bHLH-PAS proteins show similarities in the mechanisms of action [35,36].…”

Section: Molecular Insightsmentioning

confidence: 99%

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms

Bonati

Corrada

Tagliabue

et al. 2017

Current Opinion in Toxicology

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Molecular modeling has given important contributions to elucidation of the main stages in the AhR signal transduction pathway. Despite the lack of experimentally determined structures of the AhR functional domains, information derived from homologous systems has been exploited for modeling their structure and interactions. Homology models of the AhR PASB domain have provided information on the binding cavity and contributed to elucidate species-specific differences in ligand binding. Molecular Docking simulations of the ligand binding process have given insights into differences in binding of diverse agonists, antagonists, and selective AhR modulators, and their application to virtual screening of large databases of compounds have allowed identification of novel AhR ligands. Recently available structural information on protein-protein and protein-DNA complexes of other bHLH-PAS systems has opened the way for modeling the AhR:ARNT dimer structure and investigating the mechanisms of AhR transformation and DNA binding. Future research directions should include simulation of the protein dynamics to obtain a more reliable description of intermolecular interactions involved in signal transmission.

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Isoform-Selective and Stereoselective Inhibition of Hypoxia Inducible Factor-2

Cited by 72 publications

References 42 publications

Structural characterization of mammalian bHLH-PAS transcription factors

Structural characterization of mammalian bHLH-PAS transcription factors

A new paradigm for GERD pathogenesis. Not acid injury, but cytokine-mediated inflammation driven by HIF-2α: a potential role for targeting HIF-2α to prevent and treat reflux esophagitis

Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms

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