GDC-0575

GDC-0575 (ARRY-575, RG7741) is a highly-selective oral small-molecule Chk1 inhibitor with an IC₅₀ of 1.2?nM. IC50 & Target: 1.2?nM (Chk1)^[1] In Vitro: 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^[1]. 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^[2]. CHK1 inhibitor GDC-0575 in combination with AraC enhances the killing of primary acute myeloid leukemia cells ex vivo by inducing apoptosis^[3]. In Vivo: GDC-0575 is active at 25 mg/kg as a single agent, but the efficacy is improved at the higher drug dose. GDC-0575 effectively blocks tumor growth in the D20 and C002 xenografts, and the effect is maintained for at least 10 days after the final dose is administered^[1].