生物活性

• 靶点	p110α IC50:15nM

• 描述The PI3K pathway is a frequently dysregulated signaling cascade in human cancer. Activating mutations in PIK3CA (encoding the p110α catalytic subunit of PI3Kα) are strongly implicated in oncogenic PI3K signaling. MLN1117 is a potent and selective oral PI3Kα isoform inhibitor (IC₅₀ of 21 nmol/L against PI3Kα) that has demonstrated > 100-fold selectivity relative to other class I PI3K family members (PI3Kβ/γ/δ) and mTOR, and a high degree of selectivity against many other kinases. MLN1117 administration in PIK3CA-mutant tumor cell lines resulted in potent PI3K pathway inhibition, blockade of cellular proliferation, and apoptosis. MLN1117 (100 – 1200 mg) exhibited moderately fast oral absorption, a generally dose proportional increase in exposure, and plasma half-life of approximately 11 hours. Preclinical studies showed MLN1117 to have low potential for disrupting glucose metabolism or for causing cardiac adverse events; in rats and monkeys, doses up to 50 mg/kg/day were well tolerated. Administration of MLN1117 also led to dose-dependent inhibition of tumor growth in murine xenograft models of human cancer (e.g., breast carcinoma) bearing PIK3CA oncogenic mutations, with corresponding inhibition of PI3K pharmacodynamic markers in tumor tissue^[3].