| XL765 is a small molecule dual-targeted PI3K/mTOR inhibitor, which inhibits PI3Kα, PI3Kβ, PI3Kδ and PI3Kγwith IC50 values of 39, 113, 43 and 9 nM, respectively. XL765 inhibits mammalian target of rapamycin (mTOR) and DNA-depended protein kinase (DNA-PK) with IC50 values of 157 and 150 nM, respectively.[1] In five glioblastoma multiforme (GBM) cell lines GBM 6, GBM 8, GBM 12, GBM 39, and GS-2, the IC50 values of XL765 are 7.5 μM, 5.7 μM, 3.7 μM, 5.0 μM and 7.7 μM, respectively.[2] In 13 pancreatic cancer cell lines, the concentrations of XL765 inducing 50% growth inhibition (GI50) are ranging from 0.5 to 5 μM. XL765 (10 μM) induces different degree of apoptosis (3-35%) in pancreatic cancer cell lines (HcG25, Panc89, PA-TU8988T, Panc2.13, MiaPaCa2, Panc8.13, Panc10.05 and BxPC-3). In two sensitive pancreatic cancer cell lines (BxPC-3 and Panc 8.13), XL765 (2.5, 5 and 10 μM) reduces levels of pAKT (Ser-473) and, in addition, treatment with XL765 reduces phosphorylation of the mTOR targets S6, S6K, and 4EBP1 significantly. The GI50 values of XL765 for the two sensitive cell lines (BxPC-3 and Panc 8.13) are 0.2 and 0.3 μM, respectively. The GI50 values of XL765 for the two resistant cell lines (Panc 2.13 and PA-TU8988T) are 2 and 1.8 μM, respectively. Besides, XL765 (5 μM) induces an increased level of LC3-II in MIAPaCa-2 cells at 72 hours post-treatment. In a BxPC-3 pancreatic cancer xenograft model, the combination of XL765 (30 mg/kg) with chloroquine results in significant inhibition of tumor growth, while XL765 (30 mg/kg) alone has no growth inhibitory effect.[3] In GBM 39 xenografts model, XL765 (30 mg/kg) decreases the tumor burden by 13-fold compared with control. When combined with temozolomide, XL765 (30 mg/kg) further decreases the tumor burden by 140-fold compared with control. XL765 (30 mg/kg) prolongs the median survival times from 55 days for control to 68 days. When combined with temozolomide, XL765 (30 mg/kg) treated group has a median survival time of 117 days.[2] |
