Abstract
PTEN and the pan phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one (LY294002) exert significant control over tumor-induced angiogenesis and tumor growth in vivo. The LY294002 compound is not a viable drug candidate due to poor pharmacologic variables of insolubility and short half-life. Herein, we describe the development and antitumor activity of a novel RGDS-conjugated LY294002 prodrug, termed SF1126, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment, resulting in enhanced delivery of the active compound to the tumor vasculature and tumor. SF1126 is water soluble, has favorable pharmacokinetics, and is well tolerated in murine systems. The capacity of SF1126 to inhibit U87MG and PC3 tumor growth was enhanced by the RGDS integrin (alpha v beta 3/alpha 5 beta 1) binding component, exhibiting increased activity compared with a false RADS-targeted prodrug, SF1326. Antitumor activity of SF1126 was associated with the pharmacokinetic accumulation of SF1126 in tumor tissue and the pharmacodynamic knockdown of phosphorylated AKT in vivo. Furthermore, SF1126 seems to exhibit both antitumor and antiangiogenic activity. The results support SF1126 as a viable pan PI3K inhibitor for phase I clinical trials in cancer and provide support for a new paradigm, the application of pan PI3K inhibitory prodrugs for the treatment of cancer.
Highlights
The phosphoinositide 3-kinase (PI3K) pathway is a target of significant interest in human cancer due to the high frequency and broad spectrum of aberrations in the pathway observed in human tumors
It should be noted that SF1126 has no detectable PI3K inhibitory activity until hydrolyzed to SF1101, which is in line with the known structure-activity relationship known to be very sensitive to substitutions of the morpholino group [1]
It has been suggested that an important component of successful application of PI3K inhibitors to cancer therapeutics will be the capacity to measure the pharmacokinetic and pharmacodynamic effects of these agents in vivo
Summary
The PI3K pathway is a target of significant interest in human cancer due to the high frequency and broad spectrum of aberrations in the pathway observed in human tumors. We sought to develop a clinically viable small molecule inhibitor against all isoforms of PI3K (pan PI3K inhibitor) This manipulation, if successful, would be tantamount to the inhibition of a larger number of cell surface receptors, which would exert a powerful. Doi:10.1158/0008-5472.CAN-07-0669 control over proliferation, migration, metastasis, apoptosis, and angiogenesis Such a pan PI3K inhibitor, 2-(4-morpholinyl)-8phenyl-4H-1benzopyran-4-one (LY294002) was reported by Vlahos over 10 years ago [1] and shown to block all classes of PI3K with the following IC50 values: (a) p110a, 720 nmol/L; (b) p110h, 306 nmol/L; (c) p110g, 1.6 Amol/L; and (d) p110y, 1.33 Amol/L [2, 3]. Considering the published literature using this compound and its desirable inhibition properties, we were motivated to explore targeted conjugates that would overcome the limitations and provide for a desirable inhibitory profile
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