Pharmacologic Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases

Abstract

Extensive evidence implicates activation of the lipid phosphatidylinositide 3-kinase (PI3K) pathway in the genesis and progression of various human cancers. PI3K inhibitors thus have considerable potential as molecular cancer therapeutics. Here, we detail the pharmacologic properties of a prototype of a new series of inhibitors of class I PI3K. PI103 is a potent inhibitor with low IC 50 values against recombinant PI3K isoforms p110A (2 nmol/L), p110B (3 nmol/L), p110D (3 nmol/L), and p110; (15 nmol/L). PI103 also inhibited TORC1 by 83.9% at 0.5 Mmol/L and exhibited an IC 50 of 14 nmol/L against DNA-PK. A high degree of selectivity for the PI3K family was shown by the lack of activity of PI103 in a panel of 70 protein kinases. PI103 potently inhibited proliferation and invasion of a wide variety of human cancer cells in vitro and showed biomarker modulation consistent with inhibition of PI3K signaling. PI103 was extensively metabolized, but distributed rapidly to tissues and tumors. This resulted in tumor growth delay in eight different human cancer xenograft models with various PI3K pathway abnormalities. Decreased phosphorylation of AKT was observed in U87MG gliomas, consistent with drug levels achieved. We also showed inhibition of invasion in orthotopic breast and ovarian cancer xenograft models and obtained evidence that PI103 has antiangiogenic potential. Despite its rapid in vivo metabolism, PI103 is a valuable tool compound for exploring the biological function of class I PI3K and importantly represents a lead for further optimization of this novel class of targeted molecular cancer therapeutic. [Cancer Res 2007;67(12):5840-50]

The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

“…In addition, it has been shown that mTOR-induced signaling can influence cellular responses to DNA damage (Proud, 2004). Interestingly, both proteins, the catalytic subunit of DNA-PK and mTOR, are also inhibited by PI-103 (Raynaud et al, 2007). Thus, the question arises which of these potential targets of PI-103 are crucial for mediating chemosensitization on treatment with DNA-damaging drugs.…”

“…As PI-103 has been reported to inhibit DNA-PK and both mTORC1 and mTORC2 complexes, besides class I PI3K (Raynaud et al, 2007), we wanted to critically analyze their individual contributions to PI-103-mediated chemosensitization. To address this point, we used both, a pharmacological and a genetic approach.…”

Lipid signalling in disease

“…Tumours with constitutively elevated PtdIns(3,4,5)P 3 (for example, owing to loss of PTEN or because of mutations in PI3K are especially sensitive to rapamycin 118 , but an important action of rapamycin-based drugs seems to be their effect on endothelial cells and angiogenesis 38 . Limited information is available concerning the in vivo isoform-specificity of novel PI3K inhibitors, and molecules with proven anti-tumour activity in xenograft models (PI-103 (REFS 119,120) and ZSTK474 (REF. 121)) are broadspectrum PI3K inhibitors, and might also owe some of their action to the inhibition of mammalian TOR (mTOR).…”

“…131). Based on the above, and on the fact that PI3K also acts downstream of the VEGF receptor, it becomes clear how PI3K inhibitors develop their anti-angiogenic activity 120 .…”

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…For example, PI103 (compound 7; Figure 2) is a pan-PI3K inhibitor with enzymatic IC 50 values in the 2 nM (PI3Ka) to 15 nM range (PI3Kg) (Fan et al, 2007;Raynaud et al, 2007). Despite its rapid in vivo metabolism, the compound, which readily distributes to tumor tissue, delays the growth of different subcutaneous human cancer xenografts.…”