生物活性

• 描述Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that play a central role in the control of cancer cell growth, proliferation, and metastasis. PI3K is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). PQR309, a potent pan-class I PI3K inhibitor, targets mTOR kinase in a balanced fashion at higher concentrations. And it displays a mTOR/PI3Kα K_i selectivity ratio in the range of 3–8^[1]. In 49 lymphoma cell lines, PQR309 showed in vitro activity in most of them tested with a median IC₅₀ value of 233 nmol/L (95% CI, 174–324 nmol/L). The arrest in proliferation was mainly due to cell cycle arrest with a block in G₁ rather than to apoptosis, limited to only 2/7 cell lines^[2]. The half-life of 5–8 h and an AUC_0.25–12 of around 14000 h·ng/mL contributed to an excellent oral bioavailability of PQR309 (>50%). Male Beagle dogs, exposed to PQR309 at 10 mg/kg po, showed maximal drug plasma concentrations C_max of 583 ng/mL (approximately 1.5 μM) after 60–90 min and a half-life of >7 h, which results in drug levels of approximately 0.38 μM (150 ng/mL) after 24 h. The oral bioavailability of PQR309 in male Beagle dogs was estimated to be 23%^[1].
• 作用机制One morpholine of PQR309 forms a hydrogen bridge with the backbone amide of Val882, a well-known and crucial interaction^[1].