(Aryloxyacetylamino)benzoic Acid Analogues:  A New Class of Hypoxia-Inducible Factor-1 Inhibitors

Lee, Kyeong; Lee, Jeong Hyung; Boovanahalli, Shanthaveerappa K.; Jin, Yinglan; Lee, Mijeoung; Jin, Xuejun; Kim, Jin Hwan; Hong, Young-Shick; Lee, Jun Young

doi:10.1021/jm0610292

Cited by 116 publications

(93 citation statements)

References 27 publications

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“…11). It is important to notice here that D1 and DLC27 are highly original and readily accessible scaffolds, with only one biological application recently reported for DLC27 (15). The docking of DLC27 on Nef was performed (SI Fig.…”

Section: Resultsmentioning

confidence: 99%

Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Betzi

Restouin

Opi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

109

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Protein-protein recognition is the cornerstone of multiple cellular and pathological functions. Therefore, protein-protein interaction inhibition (2P2I) is endowed with great therapeutic potential despite the initial belief that 2P2I was refractory to small-molecule intervention. Improved knowledge of complex molecular binding surfaces has recently stimulated renewed interest for 2P2I, especially after identification of ''hot spots'' and first inhibitory compounds. However, the combination of target complexity and lack of starting compound has thwarted experimental results and created intellectual barriers. Here we combined virtual and experimental screening when no previously known inhibitors can be used as starting point in a structure-based research program that targets an SH3 binding surface of the HIV type I Nef protein. High-throughput docking and application of a pharmacophoric filter on one hand and search for analogy on the other hand identified drug-like compounds that were further confirmed to bind Nef in the micromolar range (isothermal titration calorimetry), to target the Nef SH3 binding surface (NMR experiments), and to efficiently compete for Nef-SH3 interactions (cell-based assay, GST pull-down). Initial identification of these compounds by virtual screening was validated by screening of the very same library of compounds in the cell-based assay, demonstrating that a significant enrichment factor was attained by the in silico screening. To our knowledge, our results identify the first set of drug-like compounds that functionally target the HIV-1 Nef SH3 binding surface and provide the basis for a powerful discovery process that should help to speed up 2P2I strategies and open avenues for new class of antiviral molecules.drug design ͉ Src homology 3 ͉ docking ͉ scoring function ͉ NMR

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Section: Resultsmentioning

confidence: 99%

Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Betzi

Restouin

Opi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Because of recent clinical (13) and experimental (16,17) evidence that hypoxic conditions promote fibrogenesis, we sought to determine the potential interaction between TGF-␤-and hypoxia-stimulated signaling. TGF-␤1 increased HIF-1␣ expression through a mechanism dependent on the kinase activity of T␤RI.…”

Section: Discussionmentioning

confidence: 99%

“…Some evidence suggests synergistic and possibly cooperative binding of Smad3 and HIF-1␣ at the promoter regions for vascular endothelial growth factor (VEGF), endoglin, and Sp1 (20,29,31). However, while hypoxia has been shown to increase fibrosis, TGF-␤ production, and Smad expression/activity (2,8,17,43), the synergy or interaction of Smad activity with simultaneous HIF-1␣ upregulation is not well-characterized. Nonetheless, animal studies developed strong evidentiary support for the hypothesis that, during progressive kidney disease, renal ischemia promotes fibrosis through synergy between HIF-1␣ and Smads.…”

mentioning

confidence: 99%

Interdependence of HIF-1α and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression

Basu

Hubchak²,

Hayashida

et al. 2011

American Journal of Physiology-Renal Physiology

127

119

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“…To determine if HIF-1␣ is implicated in CXCR4 induction by HRG, we first used the HIF-1␣ inhibitor SC205346 (67). As shown in Fig.…”

Section: Hrg Sensitizes Breast Cancer Cells To Sdf-1-induced Rac1 Actmentioning

confidence: 99%

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

López‐Haber

Barrio-Real

Casado‐Medrano

et al. 2016

Molecular and Cellular Biology

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The growth factor heregulin (HRG), a ligand of ErbB3 and ErbB4 receptors, contributes to breast cancer development and the promotion of metastatic disease, and its expression in breast tumors has been associated with poor clinical outcome and resistance to therapy. In this study, we found that breast cancer cells exposed to sustained HRG treatment show markedly enhanced Rac1 activation and migratory activity in response to the CXCR4 ligand SDF-1/CXCL12, effects mediated by P-Rex1, a Rac-guanine nucleotide exchange factor (GEF) aberrantly expressed in breast cancer. Notably, HRG treatment upregulates surface expression levels of CXCR4, a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis and an indicator of poor prognosis in breast cancer patients. A detailed mechanistic analysis revealed that CXCR4 upregulation and sensitization of the Rac response/motility by HRG are mediated by the transcription factor hypoxia-inducible factor 1␣ (HIF-1␣) via ErbB3 and independently of ErbB4. HRG caused prominent induction in the nuclear expression of HIF-1␣, which transcriptionally activates the CXCR4 gene via binding to a responsive element located in positions ؊1376 to ؊1372 in the CXCR4 promoter, as revealed by mutagenesis analysis and chromatin immunoprecipitation (ChIP). Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1␣-mediated transcriptional induction of CXCR4. E rbB receptors are known to play key roles in cell proliferation, survival, and motility and have been widely implicated in the initiation and progression of cancer. Members of this family of transmembrane tyrosine kinases include epidermal growth factor receptors (EGFR) (ErbB1/HER1), ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. Ligands with distinctive affinities for ErbB receptors promote their homo-and heterodimerization, leading to stimulation of intrinsic tyrosine kinase activity; recruitment of adaptors and effectors to autophosphorylated tyrosine sites; and activation of key signaling cascades, namely, the phosphatidylinositol-3 kinase (PI3K)/Akt, extracellular signal regulated kinase (ERK), and protein kinase C (PKC) pathways (1-4). Dysregulation of the ErbB signaling pathway is a common alteration in human cancer, and it occurs largely as a consequence of gain-offunction mutations (e.g., EGFR); gene amplification (e.g., ErbB2); and/or overexpression of ErbB ligands, such as EGF and transforming growth factor alpha (TGF␣) (EGFR ligands) and heregulin-1/neuregulin-1 (HRG) (ErbB3/ErbB4 ligand) (5-10).ErbB3 has been shown to be crucially important in breast cancer progression. This receptor is catalytically inactive, and hence, its signaling capacity depends entirely on dimerization with other catalytically competent ErbB partners. ErbB2, the only orphan member of the ErbB receptor family, is the preferred dimerization partner for ErbB3, and the ErbB2/ErbB3 heterodimer, which signals preferentially through PI3K, is regarded as a major oncog...

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(Aryloxyacetylamino)benzoic Acid Analogues: A New Class of Hypoxia-Inducible Factor-1 Inhibitors

Cited by 116 publications

References 27 publications

Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Interdependence of HIF-1α and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

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