by Kansas Staff | Oct 21 2012
CHARACTERIZATION of PI-103
So far, there are a lot of PI3K isozyme-selective allosteric inhibitors that have been reported. For example, PIK-75 is a p110alpha-specific inhibitor, TGX-221 is a p110beta-specific inhibitor and IC87114 is a p110delta-specific inhibitor. These PI3K inhibitors are promising agents in the treatment of cancer and other diseases, and PI-103 is one of them. PI-103 is a potent, cell-permeable, ATP-competitive class I PI3K inhibitor. The structure analysis indicates that PI-103 is a pyridinylfuranopyrimidine molecule and ATP-competitive PI3K inhibitor. PI-103 has the solubility around 24 mg/mL in both dimethyl sulfoxide (DMSO), however it is scarcely soluble in ethanol and water with solubility of less than 1 mg/mL. And the approximate price of PI-103 is $151 per 10 mg and $466 per 50 mg in selleckchem.com, and PI-103 price may vary according to the proportion purity of the preparation and/or from one PI-103 supplier to different ones.
IN VITRO ACTIVITIES
Kinase assays demonstrates that PI-103 shows potent inhibitory activities against recombinant PI3K isoforms including p110-alpha, p110-beta, p110-delta, and p110-gamma with IC50 of 2 nmol/L, 3 nmol/L, 3 nmol/L and 15 nmol/L, respectively. At the same time,PI-103 also inhibited the activities of DNA-PK with IC50 of 14 nmol/L, and inhibits mTORC1 by 83.9%at 0.5 μmol/L.  In vitro, PI-103 treatment results in a time- and concentration-dependent decrease in phosphorylation of AKT Ser473 and Thr308 and GSK3β Ser9 in a panel of human cancer cell lines such as HCT116 human colorectal carcinoma, U87MG glioblastoma and PC3 prostate cancer cells. Consistent with inhibition of PI3K signaling, PI-103 potently inhibits proliferation and invasion of a wide variety of human cancer cells.  In respect to combination application, cooperative inhibition of EGFR and mTOR by erlotinib and PI-103 lead to increased arrest growth of PTEN mt human glioma cells.  Combination treatment of PI-103 and radiation enhances the G(2)-M delay observed after irradiation in cancer cells.  In hepatocellular carcinoma (HCC), PI-103 in combination with sorafenib significantly inhibit EGF-stimulated Huh7 proliferation by blocking both Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. 
IN VIVO ACTIVITIES
In vivo, PI-103 exhibits potent antitumor activity in mice bearing PTEN null U87MG glioblastoma, PC3 prostate, and MDA-MB-468 breast carcinomas and the PIK3CA mutant HCT 116 colon carcinoma cells. Moreover, PI-103 also produces inhibitory effects on cell migration, invasion, and angiogenesis.  In respect to combination therapy, combination of Sorafenib and PI-103 are demonstrated to more efficiently inhibits tumorigenesis as compared to mono-drug treatments.  These studies support the potential clinical use of PI-103 as a partner for conventional drugs. The studies of clinical trails about PI-103 has been elaborated in the previous article.
 Raynaud FI, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007, 67(12), 5840-5850.
 Fan QW, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007, 67(17), 7960-7965.
 Prevo R, et al. Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res. 2008, 68(14), 5915-5923.
 Gedaly R, et al. PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010, 30(12), 4951-4958.
 Gedaly R, et al. The role of PI3K/mTOR inhibition in combination with sorafenib in hepatocellular carcinoma treatment. Anticancer Res. 2012, 32(7), 2531-2536.
|Cat.No.||Product Name||Information||Publications||Customer Product Validation|
|S1205||PIK-75||PIK-75 is a p110α inhibitor with IC50 of 5.8 nM (200-fold more potently than p110β), isoform-specific mutants at Ser773, and also potently inhibits DNA-PK with IC50 of 2 nM in cell-free assays.||(11)||(5)|
|S1169||TGX-221||TGX-221 is a p110β-specific inhibitor with IC50 of 5 nM in a cell-free assay, 1000-fold more selective for p110β than p110α.||(27)||(5)|
|S1268||IC-87114||IC-87114 is a selective PI3Kδ inhibitor with IC50 of 0.5 μM in a cell-free assay, 58-fold more selective for PI3Kδ than PI3Kγ, and over 100-fold more selective than PI3Kα/β.||(17)||(3)|
|S1038||PI-103||PI-103 is a multi-targeted PI3K inhibitor for p110α/β/δ/γ with IC50 of 2 nM/3 nM/3 nM/15 nM in cell-free assays, less potent to mTOR/DNA-PK with IC50 of 30 nM/23 nM.||(21)||(4)|
|S1023||Erlotinib HCl (OSI-744)||Erlotinib HCl (OSI-744) is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.||(72)||(15)|
|S1040||Sorafenib Tosylate||Sorafenib Tosylate is a multikinase inhibitor of Raf-1, B-Raf and VEGFR-2 with IC50 of 6 nM, 22 nM and 90 nM in cell-free assays, respectively.||(40)||(4)|