A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity

Joseph R. Garlich, Pradip De, Nandini Dey, Dong Su Jing, Xiaodong Peng, Antoinette Miller, Ravoori Murali, Yiling Lu, Gordon Mills, Vikas Kundra, H. K. Shu, Qiong Peng, Donald L. Durden

Research output: Contribution to journalArticle

230 Citations (Scopus)

Abstract

PTEN and the pan phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1benzopyran-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 (αvβ3/α5β1) 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.

Original languageEnglish (US)
Pages (from-to)206-215
Number of pages10
JournalCancer Research
Volume68
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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1-Phosphatidylinositol 4-Kinase
Prodrugs
Blood Vessels
Neoplasms
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Integrins
Pharmacokinetics
SF 1126
Clinical Trials, Phase I
Growth
Solubility
Half-Life
Water

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. / Garlich, Joseph R.; De, Pradip; Dey, Nandini; Jing, Dong Su; Peng, Xiaodong; Miller, Antoinette; Murali, Ravoori; Lu, Yiling; Mills, Gordon; Kundra, Vikas; Shu, H. K.; Peng, Qiong; Durden, Donald L.

In: Cancer Research, Vol. 68, No. 1, 01.01.2008, p. 206-215.

Research output: Contribution to journalArticle

Garlich, JR, De, P, Dey, N, Jing, DS, Peng, X, Miller, A, Murali, R, Lu, Y, Mills, G, Kundra, V, Shu, HK, Peng, Q & Durden, DL 2008, 'A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity', Cancer Research, vol. 68, no. 1, pp. 206-215. https://doi.org/10.1158/0008-5472.CAN-07-0669
Garlich, Joseph R. ; De, Pradip ; Dey, Nandini ; Jing, Dong Su ; Peng, Xiaodong ; Miller, Antoinette ; Murali, Ravoori ; Lu, Yiling ; Mills, Gordon ; Kundra, Vikas ; Shu, H. K. ; Peng, Qiong ; Durden, Donald L. / A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. In: Cancer Research. 2008 ; Vol. 68, No. 1. pp. 206-215.
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