Therapeutics: Checkpoint kinase 1 (Chk1; CHEK1)

Cell culture and mouse studies identified a pyrazine-2-carbonitrile-based Chk1 inhibitor that could help treat cancer. Chemical synthesis and in vitro testing of pyrazine-2-carbonitrile analogs identified a compound that inhibited Chk1 phosphorylation activity with an IC50 of 1.3 nM and inhibited DNA damage-induced cell cycle arrest in a human colon cancer cell line with an IC50 of 30 nM. In a mouse model of neuroblastoma, the compound decreased tumor growth compared with vehicle. In a mouse model of pancreatic ductal adenocarcinoma (PDAC) and a mouse xenograft model of colon cancer, the compound plus Gemzar gemcitabine decreased tumor growth compared with either agent alone. Next steps could include testing the compound's effects on survival in the cancer models.

Eli Lilly and Co. markets Gemzar, a nucleoside analog that inhibits DNA synthesis, to treat breast, pancreatic and ovarian cancers and non-small cell lung cancer (NSCLC) and has the compound in Phase III testing to treat biliary and cervical cancers and Phase II testing to treat bladder cancer. ...