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Ref Type Journal Article
PMID (26141948)
Authors King C, Diaz HB, McNeely S, Barnard D, Dempsey J, Blosser W, Beckmann R, Barda D, Marshall MS
Title LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms.
Abstract Text CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Drug Name Trade Name Synonyms Drug Classes Drug Description
Prexasertib LY2606368|IC-83|ACR-368|ACR368|ACR 368 CHK1 Inhibitor 17 Prexasertib (LY2606368) inhibits checkpoint kinase 1 (Chk1), which may result in accumulation of DNA damage and decreased tumor growth (PMID: 26141948, PMID: 28270495, PMID: 32539469, PMID: 32510664).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CHEK1 positive lung non-small cell carcinoma predicted - sensitive Prexasertib Preclinical - Cell line xenograft Actionable In a preclinical study, Prexasertib (LY2606368) increased apoptosis of non-small cell lung cancer (NSCLC) cells in culture, and inhibited Chek1 phosphorylation, induced DNA damage, and reduced tumor growth in a NSCLC cell line xenograft model (PMID: 26141948). 26141948