In vitro activity: GDC-0575 (also called ARRY-575, RG7741) is a novle, potent and selective inhibitor of CHK1 which specifically binds to and inhibits CHK1 with an IC50 of 1.2 nM. This allows tumor cells to bypass CHK1-dependent cell cycle arrest in the S and G2/M phases, which permits the cells to undergo DNA repair prior to enter into mitosis. CHK1 is an ATP-dependent serine-threonine kinase that phosphorylates cdc25 phosphatases in response to DNA damage. Therefore, CHK1 inhibition may sensitize tumor cells to the DNA damaging effects of certain chemotherapeutic agents.

Kinase Assay: GDC-0575 (also called ARRY-575, RG7741) is a novle, potent and selective inhibitor of CHK1 which specifically binds to and inhibits CHK1 with an IC50 of 1.2 nM.

Cell Assay: GDC-0575 is significantly more potent in promoting DNA damage, replication stress and cell death than V158411, LY2603618, and MK-8776 in a panel of melanoma cell lines. GDC-0575 abrogates DNA damage-induced S and G2–M checkpoints, exacerbates DNA double-strand breaks and induces apoptosis in STS cells. GDC-0575 has a synergistic or additive effect together with gemcitabine. CHK1 inhibitor GDC-0575 in combination with AraC enhances the killing of primary acute myeloid leukemia cells ex vivo by inducing apoptosis.