Targeted cancer therapies based on the inhibition of DNA strand break repair.
Both DNA double- and single-strand break repair are highly coordinated processes utilizing signal transduction cascades and post-translational modifications such as phosphorylation, acetylation and ADP ribosylation. 'Drugable' targets within these networks have been identified that could potentially lead to novel therapeutic approaches within the oncology arena. Key regulators within these signalling cascades, such as DNA-dependent protein kinase, ataxia-telangiectasia mutated, checkpoint kinase 1 (CHK1), checkpoint kinase 2 (CHK2) and poly(ADP-ribose) polymerase, use either ATP or nicotinamide adenine dinucleotide for their enzymatic functions and are therefore readily accessible to small molecule inhibition at their catalytic sites. A range of highly potent and selective inhibitors of these DNA damage response pathways has now been identified through drug discovery efforts, with candidate molecules either approaching or already in clinical trials. This review will describe the small molecule inhibitors and drug discovery activities that focus on DNA break repair, along with the therapeutic rationale behind chemosensitization and the concept of synthetic lethality. We will also describe the emerging clinical data coming from this exciting new approach to targeted cancer therapy.
KuDOS Pharmaceuticals Ltd, 410 Cambridge Science Park, Cambridge, UK.
M J
MJ
O'Connor
N M B
NM
Martin
G C M
GC
Smith
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010766:Phosphorylation; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011838:Radiation-Sensitizing Agents