ZSTK474

A novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], strongly inhibited the growth of tumor cells. A molecular target for ZSTK474 is PI3K. ZSTK474 directly inhibits PI3K activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1μM, ZSTK474 and LY2194002 reduced PI3K activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3β, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs.

ZSTK474 is an orally active, potent and selective, ATP-competitive inhibitor against class I phosphatidylinositol 3 kinase isoforms (PI3K IC50 in nM = 4.6/δ, 16/α, 44/β, 49/γ with = 10 μM ATP; mTOR IC50 >100 μM) with 27-fold selectivity for PI3Kα over DNA-PK. ZSTK474 inhibits PI3K-mediated signaling events in A549 cells in cultures (0.5 μM; Akt pSer473, GSK-3β pSer9, cyclinD1 expression) and induces tumor growth arrest or regression in mice in vivo (100, 200, or 400 mg/kg via daily p.o. against murine B16F10 melanoma or human A549 lung cancer, PC-3 prostate cancer, and WiDr colon cancer).

Potent antitumor activity by oral administration against murine solid tumors and human cancer xenografts