Background:

LY2606368 is a selective ATP competitive inhibitor of checkpoint kinase 1(CHK1) with IC50 value of 1.5nM in SW1990 cells [1].

CHK1 is an intracellular serine/threonine kinase that plays a role in DNA damage response pathway. The inhibitors of CHK1 are developed for the treatment of cancers. LY2606368 is an ATP-competitive inhibitor of CHK1 and is undergoing clinical trials currently. It inhibits the auto-phosphorylation of CHK1 and induces the phosphorylation of H2AX in cancer cells. In the pancreatic cell line SW1990, LY2606368 significantly inhibits cell proliferation with IC50 value of 1.5nM. LY2606368 also exerts potent anti-tumor activity in SW1990 xenograft model. Besides that, in the orthotopic SKVO3 model, treatment of LY2606368 is found to inhibit tumor growth and reduce the incidence of metastases and accumulation. However, LY2606368 is only administered intravenously due to its poor oral bioavailability [1, 2 and 3].

参考文献:
[1] Wu W, Bi C, Bence A K, et al. Antitumor activity of Chk1 inhibitor LY2606368 as a single agent in SW1990 human pancreas orthotopic tumor model. Cancer Research, 2012, 72(8 Supplement): 1776.
[2] Lainchbury M, Matthews T P, McHardy T, et al. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino) pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. Journal of medicinal chemistry, 2012, 55(22): 10229-10240.
[3] McNeely S C, Burke T F, DurlandBusbice S, et al. Abstract A108: LY2606368, a second generation Chk1 inhibitor, inhibits growth of ovarian carcinoma xenografts either as monotherapy or in combination with standard-of-care agents. Molecular Cancer Therapeutics, 2011, 10(Supplement 1): A108.