Abstract
The catalytic activity of DNA-dependent protein kinase (DNA-PK) is central to its ability to repair lethal DNAdouble strand breaks (DSBs). This includes repair of DSB lesions following therapeutic treatment of cancer cells or resulting from oxidative stress or oncogene-induced transcription. As a tactic to induce tumour chemo- and radio-sensitisation, numerous attempts have been made to identify small molecule inhibitors of DNA-PK activity. This review examines the structures of known reversible and irreversible inhibitors, including those based upon chromen-4-one, arylmorpholine, and benzaldehyde scaffolds. VX-984 and M3814 are recent examples of DNA-PK catalytic inhibitors that have progressed into clinical development, the results from which should help to further advance our understanding of whether this approach represents a promising therapeutic strategy for the treatment of cancer.
Highlights
DNA double-strand breaks (DSBs) are a highly toxic form of DNA damage that can be caused by reactive oxygen species (ROS) naturally occurring in eukaryotic cells as well as exogenous stimuli, such as ionising radiation
The active DNA-PK complex is composed of a catalytic serine/threonine protein kinase (DNA-PKcs) and two heterodimeric subunits (Ku70 and Ku80) which bind to the DSB and direct the catalytic subunit to the site requiring repair [1,2]
Once the Ku heterodimer has bound to the site of a DSB, recruitment of the DNA-PKcs takes place leading to a shift in the conformation of the heterodimer which simultaneously tethers the broken ends of the strands together and stimulates kinase activity [7,8]
Summary
DNA double-strand breaks (DSBs) are a highly toxic form of DNA damage that can be caused by reactive oxygen species (ROS) naturally occurring in eukaryotic cells as well as exogenous stimuli, such as ionising radiation. The activity of this sterol-like structure and its mode of interaction made it an interesting early tool compound, the relative structural complexity of wortmannin, together with its irreversible inhibition and poor selectively, limit its potential as a drug molecule. Despite these limitations, wortmannin was used to demonstrate a 3-5fold enhancement of IR-induced cytotoxicity and an inhibition of IRinduced DSB repair in Chinese hamster ovary cells [18]. The key role of the morpholine substituent of 3 was later substantiated by X-ray crystallography, when the structure of 3 in complex with human PI3Kγ revealed that the morpholine oxygen makes a hydrogen bond interaction with the backbone amide group of Val-882 within the ATP-binding domain of the kinase (Figure 1) [16]
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