Publication details
Selective Inhibition of Chk1 and Its Synthetic Lethality in Cancer Cells
| Authors | |
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| Year of publication | 2016 |
| Type | Appeared in Conference without Proceedings |
| Citation | |
| Description | One of the key players in genome surveillance pathways is a protein kinase, Checkpoint Kinase 1 (Chk1). Chk1 is a serine threonine effector kinase and it responds to a wide range of DNA replication stress and various forms of DNA damage, especially to single stranded DNA (ssDNA).Hence, Chk1 represents druggable molecular target for inhibition following replication stress induced by chemotherapeutic agents. Such lethal interaction leads to enhanced sensitivity of cancer cells with additional burden of damaged DNA, without cytotoxic effects to the normal cells.We have been able to develop a more potent and potential metabolically stable analog of SCH900776, OH209EN1 which phenocopies short interfering RNA-mediated CHK1 ablation and genetically interacts with DNA antimetabolite agents to sensitize a broad range of cancer cells. OH209EN1 rapidly suppresses accumulation of Chk1-p296 auto-phosphorylation following DNA damaging agents and also induces fatal amount of Double Strand Breaks (DSBs) accumulation as assessed by ?H2AX. These results suggest that the new analog OH209EN1 may be used as a tool to elucidate the role of Chk1 at the replication checkpoint and provide an enhanced therapeutic window for combinational therapy in near future. Moreover, exploring synthetic lethal interactions between DNA repair genes upon Chk1 inhibition could find wide appliance for the treatment of malignancies with particular genetic defect and provide an opportunity for monotherapy. |