GDC-0575 (ARRY-575) is a highly-selective oral small-molecule Chk1 inhibitor(IC50 of 1.2 nM).

Chk1:1.2 nM

相较于V158411、LY2603618和MK-8776，GDC-0575在促进DNA损伤、复制应激和细胞死亡方面在一组黑色素瘤细胞系中显示出显著更高的效力[1]。

CHK1抑制剂（CHK1i）GDC-0575能够增强AraC对AML细胞的杀伤作用，无论是在体内还是在体外，从而消除了涉及DNA修复的任何潜在化疗抗性机制。重要的是，这种化合物组合不会影响正常的长期造血干细胞/祖细胞[2]。

For in vivo experiments, aliquots of GDC-0575 (10 mg/mL) were stored at ?20℃and diluted in 100 mM sodium citrate buffer immediately prior to each experiment. GDC-0575 was used at 1.8 mg/ml for female mice (~25 g) and 2.6 mg/ml for male mice (~35 g) via oral gavage (final concentration 7.5 mg/kg). For in vitro experiments, aliquots of GDC-0575 (100 μM) were stored at ?20 ℃ and used at a final concentration of 100 nM. AraC (Cytosine β-D-arabinofuranoside C1768, Sigma) was used at 10 mg/kg (commonly used in clinical practice) for in vivo and at 100 nM and 500 nM for in vitro experiments. For in vivo experiments, toxicity of GDC-0575 was assessed in non-engrafted NSG mice using a range of concentrations of GDC-0575 in combination with AraC. 7.5 mg/kg GDC-0575 was the highest concentration to have no significant or lasting adverse effects in mice. Similarly, for in vitro experiments, 100 nM GDC-0575 in combination with 500 nM AraC was the highest concentration non-cytotoxic to MS5 stoma cell. ATR inhibitor was used at a final concentration of 0.5 μM[2].