Reference Detail

Ref Type

Journal Article

PMID

(18172313)

Authors

Garlich JR, De P, Dey N, Su JD, Peng X, Miller A, Murali R, Lu Y, Mills GB, Kundra V, Shu HK, Peng Q, Durden DL

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	68	1	2008 Jan 01	206-15	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN loss	prostate cancer	sensitive	SF1126	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a glioblastoma cell line harboring PTEN loss (PMID: 24634413) was sensitive to SF1126, demonstrating a 76% decrease in tumor growth in cell line xenograft models (PMID: 18172313).	18172313 24634413
PTEN inact mut	glioblastoma	sensitive	SF1126	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a glioblastoma cell line harboring a PTEN inactivating mutation (PMID: 24634413) was sensitive to SF1126, demonstrating inhibition of tumor growth in cell line xenograft models (PMID: 18172313).	18172313 24634413