Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist

Tavera-Mendoza, Luz E.; Quach, Tan D.; Dabbas, Basel; Hudon, Jonathan; Liao, Xiaohong; Palijan, Ana; Gleason, James L.; White, John H.

doi:10.1073/pnas.0709279105

Cited by 64 publications

(55 citation statements)

References 44 publications

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“…1A). We anticipated that these engineered molecules would fit well into the substrate-binding pocket of HDACs and would also interact with zinc at the active site to disrupt enzyme activity, yet still retain their ability to compete with ATP binding and function as RTK inhibitors (14,15). Confirming the effectiveness of this approach, we showed that one of the best compounds, CUDC-101, inhibits EGFR and HER2 kinase as well as HDAC enzyme activities with high potency (2.4, 16.4, and 4.2 nmol/L, respectively; Table 1).…”

Section: Resultsmentioning

confidence: 99%

CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity

et al. 2010

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Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. ©2010 AACR.

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Section: Resultsmentioning

confidence: 99%

CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity

et al. 2010

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“…In the first instance, we compared all the VDR peaks within §5 kb of 1a, 25 www.tandfonline.comnot contain DR3-types motif using Multiple Em for Motif Elicitation (MEME). 64 The binding motif of ZNF263 was significantly enriched in VDR peaks flanking both mRNA and miRNA genes.…”

Section: Vdr Binding Patterns Around Mirna and Mrnamentioning

confidence: 99%

VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription

et al. 2015

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The Vitamin D Receptor (VDR) is a member of the nuclear receptor superfamily and is of therapeutic interest in cancer and other settings. Regulation of microRNA (miRNA) by the VDR appears to be important to mediate its actions, for example, to control cell growth. To identify if and to what extent VDR-regulated miRNA patterns change in prostate cancer progression, we undertook miRNA microarray analyses in 7 cell models representing non-malignant and malignant prostate cells (RWPE-1, RWPE-2, HPr1, HPr1AR, LNCaP, LNCaP-C4-2, and PC-3). To focus on primary VDR regulatory events, we undertook expression analyses after 30 minutes treatment with 1a,25(OH) 2 D 3 . Across all models, 111 miRNAs were significantly modulated by 1a,25(OH) 2 D 3 treatment. Of these, only 5 miRNAs were modulated in more than one cell model, and of these, only 3 miRNAs were modulated in the same direction. The patterns of miRNA regulation, and the networks they targeted, significantly distinguished the different cell types. Integration of 1a,25 (OH) 2 D 3 -regulated miRNAs with published VDR ChIP-seq data showed significant enrichment of VDR peaks in flanking regions of miRNAs. Furthermore, mRNA and miRNA expression analyses in non-malignant RWPE-1 cells revealed patterns of miRNA and mRNA co-regulation; specifically, 13 significant reciprocal patterns were identified and these patterns were also observed in TCGA prostate cancer data. Lastly, motif search analysis revealed differential motif enrichment within VDR peaks flanking mRNA compared to miRNA genes. Together, this study revealed that miRNAs are rapidly regulated in a highly cell-type specific manner, and are significantly co-integrated with mRNA regulation.

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“…Samples were immunoprecipitated with ␣-IgG, ␣-KLF6 (37-8400, SC-7158), or ␣-FLAG (F1804), and protein A/G-agarose beads overnight at 4°C. Beads were washed in lysis buffer (4 times), boiled in Laemmli buffer, and Western blotted as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

Ligand-dependent Corepressor (LCoR) Recruitment by Krüppel-like Factor 6 (KLF6) Regulates Expression of the Cyclin-dependent Kinase Inhibitor CDKN1A Gene

Calderon

Verway

et al. 2012

Journal of Biological Chemistry

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Background: Ligand-dependent corepressor (LCoR) was identified as a repressor of nuclear hormone receptors. Results: A screen for new interacting factors revealed that LCoR acts with Krüppel-like factor 6 (KLF6) to repress CDKN1A gene transcription. Conclusion: KLF6 inhibits gene transcription by tethering a complex of proteins including LCoR to DNA. Significance: Identification of a novel mechanism of action of LCoR, independent of nuclear receptors, with potential implications for prostate cancer.

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Incorporation of histone deacetylase inhibition into the structure of a nuclear receptor agonist

Cited by 64 publications

References 44 publications

CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity

CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity

VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription

Ligand-dependent Corepressor (LCoR) Recruitment by Krüppel-like Factor 6 (KLF6) Regulates Expression of the Cyclin-dependent Kinase Inhibitor CDKN1A Gene

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