Identification of the KDM2/7 histone lysine demethylase subfamily inhibitor and its antiproliferative activity. by Suzuki, T, Ozasa, H, Itoh, Y, Zhan, P, Sawada, H, Mino, K, Walport, L, Ohkubo, R, Kawamura, A, Yonezawa, M, Tsukada, Y, Tumber, A, Nakagawa, H, Hasegawa, M, Sasaki, R, Mizukami, T, Schofield, C, Miyata, N

“…While inhibitors of KDM4s did not show any effect on cancer cells tested, the KDM2/7-subfamily inhibitor 9 exerted antiproliferative activity, indicating the potential for KDM2/7 inhibitors as anticancer agents.…”

Targeting histone lysine demethylases - Progress, challenges, and the future. by Thinnes, C, England, K, Kawamura, A, Chowdhury, R, Schofield, C, Hopkinson, R

“…In humans, N(ε)-methyllysine residue demethylation is catalysed by two distinct subfamilies of demethylases (KDMs), the flavin-dependent KDM1 subfamily and the 2-oxoglutarate- (2OG) dependent JmjC subfamily, which both employ oxidative mechanisms. …”

JmjC ‐domain‐containing histone demethylases by Højrup, C, Coleman, OD, Bukowski, J-P, Clausen, RP, Kawamura, A

“…It overviews the different inhibitor development strategies employed for targeting the JmjC domain of KDMs and highlights some of the subfamily‐targeted inhibitors reported to date. Due to the different domain architectures between each subfamily, as well as greater diversity between the reader domains than between their respective JmjCs, it offers better opportunities for achieving selectivity.…”

Lysine-241 has a role in coupling 2OG turnover with substrate oxidation during KDM4-catalysed histone demethylation by Hancock, R, Abboud, M, Smart, T, Flashman, E, Kawamura, A, Schofield, C, Hopkinson, R

“…Lys-241 of the KDM4 subfamily is proposed to be important in oxygen binding by KDM4A. …”

Investigations on small molecule inhibitors targeting the histone H3K4 tri-methyllysine binding PHD-finger of JmjC histone demethylases by Bhushan, B, Erdmann, A, Zhang, Y, Belle, R, Johannson, C, Oppermann, U, Hopkinson, R, Schofield, C, Kawamura, A

“…Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors.…”

Investigating the inhibitor and substrate diversity of the JmjC histone demethylases by Shamo Schiller, R

“…In a cellular context, members of the KDM3 subfamily might provide a regulatory link between methylation and acylation marks. …”

Mechanistic and structural studies of KDM‐catalysed demethylation of histone 1 isotype 4 at lysine 26 by Walport, L, Hopkinson, R, Chowdhury, R, Zhang, Y, Bonnici, J, Schiller, R, Kawamura, A, Schofield, C

“…The results reveal that methylated H1.4K26 is a substrate for all members of the KDM4 subfamily and that KDM4A‐catalysed demethylation of H1.4K26me3 peptide is similarly efficient to that of H3K9me3. …”

8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors by Bavetsias, V, Lanigan, R, Ruda, G, Atrash, B, McLaughlin, M, Tumber, A, Mok, N, Le Bihan, Y, Dempster, S, Boxall, K, Jeganathan, F, Hatch, S, Savitsky, P, Velupillai, S, Krojer, T, England, K, Sejberg, J, Thai, C, Donovan, A, Pal, A, Scozzafava, G, Bennett, J, Kawamura, A, Johansson, C, Szykowska, A, Gileadi, C, Burgess-Brown, N, von Delft, F, Oppermann, U, Walters, Z, Shipley, J, Raynaud, F, Westaway, S, Prinjha, R, Fedorov, O, Burke, R, Schofield, C, Westwood, I, Bountra, C, Müller, S, van Montfort, R, Brennan, P, Blagg, J

“…Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.…”

The activity of JmjC histone lysine demethylase KDM4A is highly sensitive to oxygen concentrations by Hancock, R, Masson, N, Dunne, K, Flashman, E, Kawamura, A

“…Here, we report detailed analysis of the effect of oxygen availability on the activity of the KDM4 subfamily member KDM4A, importantly demonstrating a high level of O2 sensitivity both with isolated protein and in cells. …”

Studies on the interaction of the histone demethylase KDM5B with tricarboxylic acid cycle intermediates by Tarhonskaya, H, Nowak, RP, Johansson, C, Szykowska, A, Tumber, A, Hancock, RL, Lang, P, Flashman, E, Oppermann, U, Schofield, CJ, Kawamura, A

“…Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. …”

Biochemical and functional studies of the histone demethylases by Williams, S

“…Unexpected demethylation profiles were observed for the KDM4 subfamily, showing both demethylation at K4 and K27, as well as K9 and K36 (for KDM4A-C).…”

Assessing histone demethylase inhibitors in cells: lessons learned by Hatch, S, Yapp, C, Montenegro, R, Savitsky, P, Gamble, V, Tumber, A, Ruda, G, Bavetsias, V, Fedorov, O, Atrash, B, Raynaud, F, Lanigan, R, Carmichael, L, Tomlin, K, Burke, R, Westway, S, Brown, J, Prinjha, R, Martinez, E, Oppermann, U, Schofield, C, Bountra, C, Kawamura, A, Blagg, J, Brennan, P, Rossanese, O, Müller, S

“…<br/><br/> Results<br/> A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. …”

Molecular and Cellular Mechanisms of HIF Prolyl Hydroxylase inhibitors in Clinical Trials by Yeh, TL, Leissing, TM, Abboud, M, Thinnes, CC, Atasoylu, O, Holt-Martyn, JP, Zhang, D, Tumber, A, Lippl, K, Lohans, CT, Leung, IKH, Morcrette, H, Kawamura, A, Flashman, E, Lu, X, Ratcliffe, P, Chowdhury, R, Pugh, C, Schofield, C

“…We describe cellular, biophysical, and biochemical studies comparing four PHD inhibitors currently in clinical trials for anaemia treatment, that describe their mechanisms of action, potency against isolated enzymes and in cells, and selectivities versus representatives of other human 2OG oxygenase subfamilies. The ‘clinical’ PHD inhibitors are potent inhibitors of PHD catalyzed hydroxylation of the HIF-α oxygen dependent degradation domains (ODDs), and selective against most, but not all, representatives of other human 2OG dependent dioxygenase subfamilies. …”

Optimisation of a triazolopyridine based histone demethylase inhibitor yields a potent and selective KDM2A (FBXL11) inhibitor by England, K, Tumber, A, Krojer, T, Scozzafava, G, Ng, S, Daniel, M, Szykowska, A, Che, K, von Delft, F, Burgess-Brown, N, Kawamura, A, Schofield, C, Brennan, P

“…A potent inhibitor of the JmjC histone lysine demethylase KDM2A (compound 35, pIC50 7.2) with excellent selectivity over representatives from other KDM subfamilies has been developed; the discovery that a triazolopyridine compound binds to the active site of JmjC KDMs was followed by optimisation of the triazole substituent for KDM2A inhibition and selectivity. …”

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition. by Brem, J, van Berkel, S, Aik, W, Rydzik, A, Avison, M, Pettinati, I, Umland, K, Kawamura, A, Spencer, J, Claridge, T, McDonough, M, Schofield, C

“…The use of β-lactam antibiotics is compromised by resistance, which is provided by β-lactamases belonging to both metallo (MBL)- and serine (SBL)-β-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. …”