Pipeline – Chk1 (Checkpoint Kinase 1)

Many known cancer treatments cause DNA damage by either physically modifying the cell's DNA or disrupting vital cellular processes that can affect the fidelity of DNA replication and cell division leading to cell death. A significant limitation to these treatments is drug resistance. One of the most important mechanisms leading to this resistance is attributed to activation of cell cycle checkpoints which give the tumour cell time to repair damaged DNA. By preventing a particular cell cycle checkpoint, it may therefore be possible to circumvent tumour cell resistance to existing cancer treatments and augment tumour cell death caused by DNA damage. This strategy would increase the efficacy of these drugs allowing the treatment of cancer patients currently refractory to existing therapies.

Checkpoint Kinase 1 (Chk1) is a protein kinase involved in regulating cell cycle checkpoint signals that are activated in response to DNA damage and errors in DNA caused by defective replication. Specifically, the role of Chk1 in the DNA damage-induced G2/M cell cycle checkpoint has been demonstrated in a number of studies where Chk1 function has been knocked out. This involvement of Chk1 in the DNA damage-induced G2/M checkpoint provides a therapeutic strategy for cancer treatment, involving targeted inhibition of Chk1.

Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair. Over half of all cancers are functionally defective for p53, which can make them resistant to cancer treatments such as ionising radiation and certain forms of chemotherapy. These p53-deficient cells fail to arrest at the G1/S checkpoint in order to undergo apoptosis or DNA repair making them more reliant on the G2/M checkpoint for viability and replication fidelity. Blocking the function of G2/M checkpoint through inhibition of the Chk1 kinase function has been demonstrated to selectively sensitise p53-deficient cancer cells to cancer therapies.

Chk1

Sareum, in a discovery partnership with the Institute of Cancer Research (ICR) and Cancer Research Technologies, are progressing several series of selective Chk1 inhibitors as anti-cancer drug for co-administration with existing therapies.