In Vitro

Chk1 is an ATP-dependent serine-threonine kinase and a key component in the DNA replication-monitoring checkpoint system activated by double-stranded breaks (DSBs). Chk1 contributes to all currently defined cell cycle checkpoints, including G1/S, intra-S-phase, G2/M, and the mitotic spindle checkpoint. By inhibiting the activity of chk1, LY2603618 prevents the repair of DNA caused by DNA-damaging agents, thus potentiating the antitumor efficacies of various chemotherapeutic agents. However, preclinical data involving LY2603618 has not been published until now. ^[1] Inhibition of Chk1 is predicted to enhance the effects of antimetabolites, such as gemcitabine. ^[2] LY2603618 treatment impairs DNA synthesis, increases DNA damage (via mitotic defects), induces apoptosis, and has synergistic activity with pemetrexed, especially in p53 mutant tumor cells. ^[3]

In Vivo

In xenograft models, LY2603618 delays tumor growth when given in combination with pemetrexed. ^[3]

Clinical Trials

A Phase I study of to assess the effect of LY2603618 on the metabolic pathway of Desipramine is ongoing.

Features