The catalytic activity of DNA‐dependent protein kinase (DNA‐PK) is critical to its ability to repair lethal DNA double‐strand breaks (DSBs). This includes repair of DSB lesions resulting from oxidative stress, oncogene‐induced transcription, or following therapeutic treatment of cancer cells. Armed with this knowledge, many attempts have been made to identify small‐molecule inhibitors of DNA‐PK activity as an approach to induce tumour chemo‐ and radiosensitisation. This review examines the structures of known reversible and irreversible inhibitors, including those based on chromen‐4‐one, arylmorpholine, and benzaldehyde scaffolds. DNA‐PK catalytic inhibitors, such as VX‐984 (8‐[(1S)‐2‐[[6‐(4,6‐dideuterio‐2‐methylpyrimidin‐5‐yl)pyrimidin‐4‐yl]amino]‐1‐methylethyl]quinoline‐4‐carboxamide) and M3814 ((S)‐[2‐chloro‐4‐fluoro‐5‐(7‐morpholinoquinazolin‐4‐yl)phenyl]‐(6‐methoxypyridazin‐3‐yl)methanol), have now progressed into clinical development which should help to further advance our understanding of whether this approach is a promising therapeutic strategy for the treatment of cancer.

Aim: To test the hypothesis that glucokinase activators (GKAs) induce hepatic adaptations that alter intra-hepatocyte metabolite homeostasis. Methods: C57BL/6 mice on a standard rodent diet were treated with a GKA (AZD1656) acutely or chronically. Hepatocytes were isolated from the mice after 4 or 8 weeks of treatment for analysis of cellular metabolites and gene expression in response to substrate challenge. Results: Acute exposure of mice to AZD1656 or a liver-selective GKA (PF-04991532), before a glucose tolerance test, or challenge of mouse hepatocytes with GKAs ex vivo induced various Carbohydrate response element binding protein (ChREBP) target genes, including Carbohydrate response element binding protein beta isoform (ChREBP-β), Gckr and G6pc. Both glucokinase activation and ChREBP target gene induction by PF-04991532 were dependent on the chirality of the molecule, confirming a mechanism linked to glucokinase activation. Hepatocytes from mice treated with AZD1656 for 4 or 8 weeks had lower basal glucose 6-phosphate levels and improved ATP homeostasis during high substrate challenge. They also had raised basal ChREBP-β mRNA and AMPK-α mRNA (Prkaa1, Prkaa2) and progressively attenuated substrate induction of some ChREBP target genes and Prkaa1 and Prkaa2. Conclusions: Chronic GKA treatment of C57BL/6 mice for 8 weeks activates liver ChREBP and improves the resilience of hepatocytes to compromised ATP homeostasis during high-substrate challenge. These changes are associated with raised mRNA levels of ChREBP-β and both catalytic subunits of AMP-activated protein kinase.

Structure-guided expansion of a fragment hit for the ATAD2 bromodomain enabled improvement in ATAD2 inhibition and selectivity over BRD4.

Two series of inhibitors of sulfatase 2, ARSA and ARSB were designed based on biphenyl and biphenyl ether scaffolds substituted with e.g. sulfamate and carboxylate groups.