Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

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, 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 suggests 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.

Original publication

DOI

10.1016/j.ejmech.2019.05.041

Type

Journal article

Journal

Eur J Med Chem

Publication Date

01/09/2019

Volume

177

Pages

316 - 337

Keywords

Histone demethylases, KDM inhibitors, KDM4 subfamily, KDM5 subfamily, Pyridopyrimidinones, Cell Line, Tumor, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Hydrophobic and Hydrophilic Interactions, Jumonji Domain-Containing Histone Demethylases, Molecular Structure, Protein Binding, Pyridines, Pyrimidinones, Structure-Activity Relationship