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SF1126

SF1126 is a water soluble, small-molecule prodrug containing the pan-PI3K/mTOR inhibitor LY294002/SF1101 conjugated to the RGD-containing tetra-peptide SF1174 with potential antineoplastic and antiangiogenic activities. The targeting peptide SF1174 moiety of pan-PI3K/mTOR inhibitor SF1126 selectively binds to cell surface integrins and, upon cell entry, the agent is hydrolyzed to the active drug SF1101; SF1101 selectively inhibits all isoforms of phosphoinositide-3-kinase (PI3K) and other members of the PI3K superfamily, such as the mammalian target of rapamycin (mTOR) and DNA-PK. By inhibiting the PI3K signaling pathway, this agent may inhibit tumor cell and tumor endothelial cell proliferation and survival. Integrins are transmembrane cell adhesion proteins expressed on the surfaces of endothelial and tumor cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

SF1126 was designed to increase 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. see http://www.ncbi.nlm.nih.gov/pubmed/18172313.

Current developer:    Semafore Pharmaceuticals

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13. Ozbay Tuba; Durden Donald L; Liu Tongrui; O'Regan Ruth M; Nahta Rita In vitro evaluation of pan-PI3-kinase inhibitor SF1126 in trastuzumab-sensitive and trastuzumab-resistant HER2-over-expressing breast cancer cells. Cancer chemotherapy and pharmacology (2010), 65(4), 697-706. Journal code: 7806519. E-ISSN:1432-0843. PubMed ID 19636556 AN 2010034402

14. Garlich Joseph R; De Pradip; Dey Nandini; Su Jing Dong; Peng Xiaodong; Miller Antoinette; Murali Ravoori; Lu Yiling; Mills Gordon B; 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. Cancer research (2008), 68(1), 206-15. Journal code: 2984705R. E-ISSN:1538-7445. PubMed ID 18172313 AN 2008006354

15. Harvey R Donald; Lonial Sagar PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future oncology (London, England) (2007), 3(6), 639-47. Journal code: 101256629. E-ISSN:1744-8301. PubMed ID 18041916 AN 2007705338