Chk1 is a serine-threonine kinase which acts as a key regulator of important cell cycle checkpoints and central mediator of the DDR network. Chk1 regulates multiple cell-cycle phases, temporarily pausing the progression of cell replication and division in order for DNA repair processes to be undertaken. In addition, Chk1 directly activates several proteins involved in the repair of damaged DNA.
Malignant cells tolerate substantially greater levels of genomic instability than would be acceptable in healthy cells. Despite accumulating considerable DNA damage due to replicative stress or defects in DNA repair machinery, cancer cells survive and replicate via an over-reliance on select components of the DDR network, including Chk1. Consistent with this observation, inhibition of Chk1 has been shown to be synthetically lethal to cancer cells harboring functional genetic alterations in genes such as MYC, RAS, ATM, BRCA1, BRCA2 and TP53. This provides an opportunity to treat cancers with high replication stress and genomic instability with Chk1 inhibitor therapy.
Certain standard chemotherapeutic drugs (such as gemcitabine, cisplatinand topotecan) and radiotherapy also induce DNA damage in order to kill cancer cells. We believe considerable preclinical evidence supports the potential for synergy between these standard therapies and Chk1 inhibitors in combination.