Linking of 2‐Oxoglutarate and Substrate Binding Sites Enables Potent and Highly Selective Inhibition of JmjC Histone Demethylases

Woon, Esther C. Y.; Tumber, Anthony; Kawamura, Akane; Hillringhaus, Lars; Ge, Wei; Rose, Nathan R.; Jerome, H. Y.; Chan, Mun Chiang; Walport, Louise J.; Hing, Ka; Ng, Stanley S.; Marsden, Brian D.; Oppermann, U.; McDonough, Michael A.; Schofield, Christopher J.

doi:10.1002/anie.201107833

Cited by 63 publications

(52 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To investigate the selectivity of 12 against other Fe( ii )- and 2OG-dependent oxygenases, 12 was tested for inhibition against two clinically important human 2OG oxygenases, PHD2 38,39 (an oxygen sensing enzyme, which is central to hypoxic response) and JMJD2A 40,41 (jmjC histone lysine demethylase, targeted for the treatment of cancer). 12 showed IC 50s > 100 μM and >300 μM for PHD2 and JMJD2A, respectively, thus demonstrating 100–300 fold selectivity towards FTO.…”

Section: Resultsmentioning

confidence: 99%

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pathological roles of enzymes modifying histone methylation, including JmjC histone demethylases, is only beginning to be understood and these enzymes provide promising drug targets. As such, several studies have already attempted to employ structural and medicinal chemical strategies to target these enzymes for therapy [104,107–111]. As JmjC histone demethylases require oxygen as a cofactor, it is possible to speculate that histone marks can be rapidly altered when hypoxia is present.…”

Section: Discussionmentioning

confidence: 99%

Chromatin and oxygen sensing in the context of JmjC histone demethylases

Shmakova

Batie

Druker

et al. 2014

Biochemical Journal

107

View full text Add to dashboard Cite

Responding appropriately to changes in oxygen availability is essential for multicellular organism survival. Molecularly, cells have evolved intricate gene expression programmes to handle this stressful condition. Although it is appreciated that gene expression is co-ordinated by changes in transcription and translation in hypoxia, much less is known about how chromatin changes allow for transcription to take place. The missing link between co-ordinating chromatin structure and the hypoxiainduced transcriptional programme could be in the form of a class of dioxygenases called JmjC (Jumonji C) enzymes, the majority of which are histone demethylases. In the present review, we will focus on the function of JmjC histone demethylases, and how these could act as oxygen sensors for chromatin in hypoxia. The current knowledge concerning the role of JmjC histone demethylases in the process of organism development and human disease will also be reviewed.

show abstract

“…Another strategy to confer certain KDM4 selectivity was to couple a peptide mimic of the histone substrate with the 2‐OG analogue N ‐oxalyl‐ d ‐cysteine. This two‐component inhibitor could bind simultaneously the substrate and co‐substrate pockets and selectively inhibit KDM4A and KDM4E in the nanomolar range …”

Section: Introductionmentioning

confidence: 99%

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

et al. 2016

View full text Add to dashboard Cite

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.

show abstract

Linking of 2‐Oxoglutarate and Substrate Binding Sites Enables Potent and Highly Selective Inhibition of JmjC Histone Demethylases

Abstract: Select an isoform: Linking of cosubstrate and substrate binding sites enables highly selective inhibiton of isoforms of human histone lysine demethylases. The results should provide a basis for the development of potent and selective JmjC inhibitors, possibly suitable for clinical use.

Cited by 63 publications

References 27 publications

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO

Chromatin and oxygen sensing in the context of JmjC histone demethylases

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Contact Info

Product

Resources

About

Linking of 2‐Oxoglutarate and Substrate Binding Sites Enables Potent and Highly Selective Inhibition of JmjC Histone Demethylases

Abstract: Select an isoform: Linking of cosubstrate and substrate binding sites enables highly selective inhibiton of isoforms of human histone lysine demethylases. The results should provide a basis for the development of potent and selective JmjC inhibitors, possibly suitable for clinical use.

Cited by 63 publications

References 27 publications

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO

Chromatin and oxygen sensing in the context of JmjC histone demethylases

4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

Contact Info

Product

Resources

About

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO

A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N⁶-methyladenosine demethylase FTO