Diamond Publications - Search Results

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

One item found (0 items not approved).

Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays Yann-vai Le Bihan , Rachel M. Lanigan , Butrus Atrash , Mark G. Mclaughlin , Srikannathasan Velupillai , Andrew G. Malcolm , Katherine S. England , Gian Filippo Ruda , N. Yi Mok , Anthony Tumber , Kathy Tomlin , Harry Saville , Erald Shehu , Craig Mcandrew , Leanne Carmichael , James M. Bennett , Fiona Jeganathan , Paul Eve , Adam Donovan , Angela Hayes , Francesca Wood , Florence I. Raynaud , Oleg Fedorov , Paul Brennan , Rosemary Burke , Rob Van Montfort , Olivia W. Rossanese , Julian Blagg , Vassilios Bavetsias European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.041 Diamond Proposal Number(s): [20145] Open Access Show Abstract ▼ Abstract: Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, the conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggest that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.	May 2019

Instruments / Technical Area

Publication Details

Published

Actions

I02-Macromolecular Crystallography
I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)

C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays