Cell Cycle Checkpoint Kinases CHK1 and CHK2
Both CHK1 and CHK2 are key components of the DNA damage signalling network and whilst similar in name, their cellular activities are divergent.
CHK1 is important for the activation of S, G2 checkpoints in response to DNA damage and replicative stress and is involved in DNA repair. In addition, studies have shown that in tumour cells which are deficient in the tumour suppressor p53, CHK1 inhibition will sensitise these cells to genotoxic cancer treatments. Inhibitors of this kinase are therefore 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.
In collaboration with Dr Ian Collins (Medicinal chemistry Team 2), other teams in Cancer Therapeutics and Sareum Limited, Cambridge, we have used crystallographic structure-based design to optimise the biological activity of hits identified through fragment-based screening against CHK1. We developed a cascade of cellular assays, evaluated these compounds in vitro and subsequently developed robust pharmacodynamic (PD) biomarkers for compound evaluation in vivo.
This led to the identification of SAR020106 as a potent and selective inhibitor of CHK1 with in vivo activity in human tumour xenograft models and provided proof of both mechanism and concept for the project that CHK1 inhibition was therapeutically relevant. We have recently generated cell lines with resistance to both in-house and external CHK1 inhibitors and are currently investigating potential mechanisms of resistance.
Whilst there is substrate overlap between CHK1 and CHK2, the evidence that inhibition of CHK2 will also sensitise p53 deficient tumour cells to genotoxic cancer treatments remains unclear. The principal objective of the CHK2 drug discovery project was therefore to generate potent and selective inhibitors of this kinase and to use these inhibitors as chemical probes to define the correct therapeutic context for CHK2 inhibition.
This drug discovery project is in collaboration with Dr Ian Collins (Medicinal chemistry Team 2), other teams in Cancer Therapeutics and Professor Laurence Pearl (University of Sussex), who solved the first crystal structure of the CHK2 kinase domain. The CHK2 drug discovery project utilised iterative crystallography and structure-based design to identify novel potent and selective small molecule inhibitors of CHK2. We have gone on to use one of these inhibitors, CCT241533, as a tool compound to investigate the correct therapeutic context for CHK2 inhibition. These studies have led to our novel discovery that pharmacological inhibition of CHK2 may have therapeutic value when combined with inhibition of the DNA repair enzyme PARP, thus providing a potential therapeutic context for CHK2 inhibition in the clinic.