Objective

Human Jumonji C-domain (JmjC) containing histone lysine demethylases (KDMs) comprise five subfamilies (KDM2-KDM6) and are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases that remove methyl groups from methylated histone lysine substrates. KDM4A-C subfamily members mainly demethylate the H3K9Me₃/Me₂ and H3K36Me₃/Me₂ histone substrates. The KDM5 subfamily consists of four members (A-D) which specifically catalyse the demethylation of H3K4Me₃/Me₂ histone substrates. KDM4 and KDM5 subfamilies have been implicated in human malignancies including breast and prostate cancer. The reported implication of KDMs in human malignancies prompted us to undertake a research programme to discover cell penetrant, potent, and selective KDM4 subfamily inhibitors. This presentation will detail the discovery of bidentate Fe(II) chelating N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives from an HTS campaign against KDM4B, and their subsequent structure-based optimisation to a series of C8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one derivatives. Further optimization via pyrazole C4-derivatization afforded a subseries of compounds that display balanced biochemical inhibition of KDM4 and KDM5 demethylases, and selectivity over exemplars of the KDM2, KDM3, and KDM6 subfamilies. Key compounds display inhibition of both the KDM4A and KDM5B demethylases in cells.