GDC-0575 (dihydrochloride)

GDC-0575 dihydrochloride (ARRY-575 dihydrochloride) is an orally bioavailable CHK1 inhibitor, with an IC₅₀ of 1.2 nM, and has antitumor activity. IC50 & Target:IC50: 1.2 nM (CHK1)^[1] In Vitro: GDC-0575 dihydrochloride is a selective and orally bioavailable CHK1 inhibitor, with an IC₅₀ of 1.2 nM. GDC-0575 (100 nM) suppressses CHK1 activation induced by AraC by decreasing the level of Tyr15-phosphorylated CDK2. GDC-0575 (100 nM) has no effect on the viability of AML cells, but significantly reduces cell viability and induces apoptosis in combination with AraC. In addition, GDC-0575 plus AraC shows no effect on normal hematopoietic stem and progenitor cells (HSPCs)^[1]. GDC-0575 shows cytotoxic activity against most of 20 melanoma cell lines tested, but several cell lines grown as tumour sphere (TS) are relatively insensitive^[2]. In Vivo: GDC-0575 (7.5 mg/kg, p.o.) in combination with AraC alomost completely eradicates leukemic burden in mice transplanted with U937-Luc cells, and shows more efficient activity than AraC alone. Furthermore, GDC-0575 elevates the cytotoxicity of AraC in different primary AML models in vivo^[1]. GDC-0575 (25, 50 mg/kg, p.o.) dose-dependently inhibits the growth of tumor in D20 and C002 xenografts^[2].