Publication

Article Metrics

Citations


Online attention

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

DOI: 10.1016/j.ejmech.2019.05.041 DOI Help

Authors: Yann-vai Le Bihan (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Rachel M. Lanigan (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Butrus Atrash (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Mark G. Mclaughlin (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Srikannathasan Velupillai (Structural Genomics Consortium (SGC), University of Oxford) , Andrew G. Malcolm (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Katherine S. England (Structural Genomics Consortium (SGC), University of Oxford; Target Discovery Institute (TDI)) , Gian Filippo Ruda (Structural Genomics Consortium (SGC), University of Oxford) , N. Yi Mok (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Anthony Tumber (Structural Genomics Consortium (SGC), University of Oxford; Target Discovery Institute (TDI)) , Kathy Tomlin (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Harry Saville (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Erald Shehu (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Craig Mcandrew (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Leanne Carmichael (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , James M. Bennett (Structural Genomics Consortium (SGC), University of Oxford; Target Discovery Institute (TDI)) , Fiona Jeganathan (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Paul Eve (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Adam Donovan (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Angela Hayes (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Francesca Wood (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Florence I. Raynaud (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Oleg Fedorov (Structural Genomics Consortium (SGC), University of Oxford; Target Discovery Institute (TDI)) , Paul Brennan (Structural Genomics Consortium (SGC), University of Oxford; Target Discovery Institute (TDI)) , Rosemary Burke (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Rob Van Montfort (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Olivia W. Rossanese (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Julian Blagg (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research) , Vassilios Bavetsias (Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 20145

Open Access Open Access

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.

Journal Keywords: Pyridopyrimidinones; KDM4 subfamily; KDM5 subfamily; KDM inhibitors; Histone demethylases

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Documents:
j56j5j.pdf