by Adam Fox | Oct 17 2012
According to the critical roles of PI3K for cell growth and survival, a series of isoform-selective inhibitors of the PI3 kinase family, such as PI-103, PIK-90, and TGX-468 are synthesized and identified to block phosphorylation of Akt, the downstream effector of PI3 kinase in cancer cell lines. PI103 is a promising tricyclic pyridofuropyrimidine lead and chemical tool compound, and a potent inhibitor with low IC50 values against recombinant PI3K isoforms including p110alpha, p110beta, p110delta,, and p110gamma. Besides, PI-103 also produces effective inhibitory activity against mTORC1 and DNA-PK in the low concentration.  In preclinical studies, PI-103 potently inhibits proliferation and invasion of human cancer cells, and shows antiangiogenic potential. Moreover, PI-103 also enhances the induction of mitochondrial apoptosis by enhances downstream p53 signaling . 
ACTION MECHANISM OF PI-103
Action mechanism of PI-103 has been evaluated by researchers. As shown in the figure above, Class I PI3 kinase isoforms are activated by upstream ligand-bound receptor tyrosine kinases, such as insulin or IGF-1R, through interactions involving Ras and p85 regulatory subunits. Activated PI3K further initiates the signaling pathway by inducing activation of AKT, PDK1 and mTORC2, resulting in the regulation of several cellular processes. Simultaneously, PTEN phosphatase involves in the negative regulation of the PI3K pathway by depleting PIP3 levels and reduces expression of IRS-1 mediated by p70S6K. The crycrystal structure of p110γ and PI-103 suggests that the morpholino group of PI-103 forms the hydrogen bond with the hinge and that its phenol moiety binds in the affinity pocket.  As a multi-target inhibitor, PI-103 inhibits p110 and both mTORC2 and the mTORC1 in PI3K/AKT/mTOR signaling pathway. Precisely this inhibition at multiple sites, abrogates the feedback inhibition and delivers a powerful two-hit inhibition of of the PI3K pathway, resulting in an undesirable activation of PKB/Akt in cancer models and in patients.
On basis of its preclinical activities, PI-103 has been employed as a chemical tool and evoluted into many inhibitors, such as GDC-0941. And some of the derivatives are currently in human clinical trials for the treatment of cancer and other diseases. In addition, PI-103, along with a diverse array of other cell permeable, relatively drug-like PI3K inhibitors has been termed " PI3 kinome" for use in studies by scientists. These inhibitors can be used to probe mechanisms and demonstrate feasibility and consequences of pathway inhibition – into inhibitors with improved, more drug-like properties. We will continue to follow up on the new studies about PI-103 and the related combination therapy.
 Raynaud FI, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007, 67(12), 5840-5850.
 Kojima K, et al. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML. Leukemia. 2008, 22(9), 1728-1736.
 Cell. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. 2006, 125(4), 733-747
 Workman P, et al. Drugging the PI3 kinome. Nat Biotechnol. 2006, 24(7), 794-796.
|Cat.No.||Product Name||Information||Publications||Customer Product Validation|
|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)|
|S1187||PIK-90||PIK-90 is a PI3Kα/γ/δ inhibitor with IC50 of 11 nM/18 nM/58 nM, respectively, less potent to PI3Kβ.||(6)||(5)|
|S1065||Pictilisib (GDC-0941)||Pictilisib (GDC-0941) is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM in cell-free assays, with modest selectivity against p110β (11-fold) and p110γ (25-fold). Phase 2.||(58)||(8)|