ZSTK474

ZSTK474 is an ATP-competitive pan-class I PI3K inhibitor with IC₅₀s of 16 nM, 44 nM, 4.6 nM and 49 nM for PΙ3Κα, PI3Kβ, PI3Kδ and PI3Kγ, respectively. IC50 & Target:IC50: 16 nM (PI3Kα), 44 nM (PI3Kβ), 4.6 nM (PI3Kδ), 49 nM (PI3Kγ)^[1] In Vitro:Lineweaver-Burk plot analysis revealed that ZSTK474 inhibits all four PI3K isoforms in an ATP-competitive manner. The K_i values determined for the four PI3K isoforms showed that ZSTK474 inhibited the PI3Kδ isoform most effectively with a K_i of 1.8 nM, whereas the other isoforms are inhibited with 4-10-fold higher K_i values. Therefore, ZSTK474 should be regarded as a pan-PI3K inhibitor. We also determined the IC₅₀ values for inhibiting the four PI3K isoforms with ZSTK474 and LY294002. The IC₅₀ values of ZSTK474 (16, 44, 4.6 and 49 nM for PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ, respectively) are shown to be consistent with the K_i values (6.7, 10.4, 1.8 and 11.7 nM for PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ, respectively), which further supported the idea that ZSTK474 inhibits PI3Kδ most potently. Even at a concentration of 100 μM, ZSTK474 inhibits mTOR activity rather weakly^[1]. In Vivo:In mice subjected to MCAO, treatment with ZSTK474 is tested at dosages of 50, 100, 200, and 300 mg/kg. Since the 200 mg/kg dose produces significant improvement and no obvious toxic effects (P<0.01), mice are treated with ZSTK474 at a dose of 200 mg/kg/day daily for three post-MCAO days during the remaining experiments of this study. Neurological function is examined in mice suffered from MCAO followed by 24, 48, and 72 h of reperfusion. In the ZSTK474 group, neurological function scores are significantly better than the control group except the corner test^[2].