GDC-0575

GDC-0575 (ARRY-575, RG-7741) is a potent, selective and orally bioavailable Chk1 inhibitor with IC50 of 1.2 nM; enhances the killing of primary AML cells ex vivo by inducing apoptosis combined with AraC, blocks the activation of CHK1 induced by AraC via decrease in the level of Tyr15-phosphorylated CDK2 at 100 nM in AML cells.Blood Cancer Phase 1 Clinical(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. 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.(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.