Cascadian Therapeutics is investigating the utility of checkpoint kinase 1 (Chk1) inhibitors, a novel approach to cancer treatment, through a collaboration with Sentinel Oncology.
Chk1 is a protein kinase that is activated in response to DNA damage and DNA replication stress. Together with other cellular factors, Chk1 provides a coordinated "checkpoint" to arrest the cell division cycle in response to damaged DNA (Gabrielli et al., 2012). The induction of this cell cycle checkpoint enables cells to repair DNA lesions and ensures the fidelity of the cell division process.
Cancer cells commonly have mutations that reduce or eliminate the activity of DNA damage response factors that function in parallel with Chk1. These mutations make tumor cells more reliant on the activity of Chk1 to provide cell cycle checkpoint control, which represents an "Achilles heel" that can be exploited by drugs that target Chk1 (Toledo et al., 2011). This is exemplified by tumor cells that harbor mutations that inactivate the tumor suppressor p53, which is mutated in approximately 50% of all cancers. The loss of p53 alters the DNA damage response of tumor cells and makes them more sensitive to Chk1 inhibitors, producing a synergistic tumor killing effect when combined with DNA targeted chemotherapy drugs.
In pre-clinical studies, Chk1 inhibitors have been shown to inhibit tumor growth as single agents and can substantially increase the effectiveness of anti-cancer drugs that induce DNA damage or target DNA replication. The figure below demonstrates the synergy of combining chemotherapy with an Cascadian Therapeutics Chk1 kinase inhibitor in a mouse tumor model. Importantly, in this experiment the combination of the Cascadian Therapeutics Chk1 inhibitor with chemotherapy was well tolerated and produced no additional weight loss compared with chemotherapy alone.
The collaboration between Cascadian Therapeutics and Sentinel is focused on the development of a series of highly potent, selective, and orally active Chk1 inhibitors for use in combination with other cancer drugs, including chemotherapeutics and targeted signal transduction inhibitors. The program is currently at the lead optimization stage with multiple molecules identified with excellent potency and drug properties.
Defective cell cycle checkpoints as targets for anti-cancer therapies »
Gabrielli, B. et al.
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