Publication details

Exploring synthetic lethal interaction between Checkpoint Kinase 1(CHK1) and DNA replication stress



Year of publication 2014
Type Appeared in Conference without Proceedings
Description Complex networks of redundant surveillance mechanisms, namely evolutionarily conserved DNA damage response (DDR) and checkpoints, maintain genomic integrity following various genomic insults. Exploring synthetic lethal interactions between DNA repair pathways have wide appliance to the treatment of many types of malignancies. One of the key players in genome surveillance pathways is a protein kinase, CHK1. DNA damage and replication stress supposedly induces activation of CHK1, which then transduces the checkpoint signal and aids cell cycle arrest allowing time for DNA repair. Hence, CHK1 represents druggable molecular target for inhibition following replication stress induced by chemotherapeutic agents. Such synthetic lethal interaction leads to enhanced sensitivity of cancer cells with additional burden of damaged DNA, without cytotoxic effects to the normal cells. Our results suggest that in human tumor cell lines, ablation of CHK1 function by either knock down or inhibition during replication stress created by depletion of replicative DNA Polymerase ? (DNA Pol ?) or antimetabolite exposure leads to cancer cell death. SCH 900776 was identified as a highly potent and functionally optimal CHK1 inhibitor with minimal intrinsic antagonistic properties via high content screening (Guzi et al., 2011). We have been able to develop a metabolically stable analog of SCH 900776, OH209EN1 which phenocopies short interfering RNA-mediated CHK1 ablation and genetically interacts with DNA antimetabolite agents and sensitizes cancer cells approximately 4 times more efficiently. OH209EN1 rapidly suppresses accumulation of CHK1-p296 auto-phosphorylation following HU treatment and also induces fatal amount of Double Strand Breaks (DSBs) accumulation as assessed by ?H2AX. These results suggest that the new metabolically stable 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 cancer treatment in near future.

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