CHK1 and CHK2 Inhibitors

Cell Cycle Control Team

Section: Cancer Research UK Cancer Therapeutics Unit

CHK1 and CHK2 are two serine/threonine kinases involved in the induction of cell cycle checkpoints in response to DNA damage and replicative stress. CHK1 is essential for the G2/M DNA damage-induced checkpoint, and inhibitors of this kinase are expected to lead to sensitisation of tumours to both radiotherapy in the form of ionising radiation (IR) and chemotherapeutic agents which are used in the clinic for the treatment of cancer. Recent studies suggest that unlike CHK1, CHK2 is not essential for the initiation of the G2 checkpoint, and there is evidence of a functional link between the tumour suppressor p53 and CHK2. In this context, CHK2 inhibition would be predicted to reduce p53-induced apoptosis and protect normal tissues from chemotherapy. The recent discovery that activated CHK2 phosphorylates the pro-apoptotic transcription factor E2F resulting in protein stabilisation, activation and E2F-dependent apoptosis may still provide a therapeutic strategy for increasing tumour cell susceptibility to DNA damage. Inhibition of CHK2 in cancer cells with defective checkpoints, may allow tumour cells to remain proliferating and thus become more sensitive to IR or chemotherapy. Assays have therefore been developed in order to screen for inhibitors of both CHK1 and CHK2 and a number of hits have been identified that are now undergoing evaluation for further drug development. A collaboration has also been initiated with Professor L Pearl (Section of Structural Biology) to crystallise the CHK2 kinase, to aid drug development on this project.