Prexasertib (LY2606368) is an ATP-competitiveCHK1inhibitor with a Ki value of 0.9 nmol/L. For CHK2 and RSK, its IC50 values are 8 nM and 9 nM respectively in cell-free assay.
In nonclinical studies, LY2606368 induced DNA damage as measured by replication catastrophe and increases in pH2A.X, a marker of double-stranded DNA breaks. 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. In a functional assay, LY2606368 potently abrogated the G2–M checkpoint activated by doxorubicin in p53-deficient HeLa cells with an EC50 of 9 nmol/L. LY2606368 was broadly antiproliferative with IC50 values typically <50 nmol/L in the most sensitive cell lines with a minority of cell lines showing considerable resistance with IC50\'s >1,000 nmol/L. LY2606368 requires CDC25A and CDK2 to cause DNA damage.
In vivo
LY2606368 inhibited tumor growth in cancer xenografts as monotherapy and in combination with other agents. In an orthotopic SKOV3 ovarian cancer model, LY2606368 was shown to inhibit the growth of primary tumors and significantly reduce the incidence of metastases and ascites accumulation. LY2606368 also demonstrated efficacy in an SW1990 orthotopic pancreatic cancer model resulting in a 92% inhibition of primary tumor growth and the elimination of metastases to the lymphnode, spleen, and intestine.
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