title: A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity.
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.
authors.affiliation: Semafore Pharmaceuticals, Indianapolis, Indiana, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Garlich
authors.forename: Pradip
authors.initials: P
authors.lastname: De
authors.forename: Nandini
authors.initials: N
authors.lastname: Dey
authors.forename: Jing Dong
authors.initials: JD
authors.lastname: Su
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Peng
authors.forename: Antoinette
authors.initials: A
authors.lastname: Miller
authors.forename: Ravoori
authors.initials: R
authors.lastname: Murali
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Vikas
authors.initials: V
authors.lastname: Kundra
authors.forename: H-K
authors.initials: HK
authors.lastname: Shu
authors.forename: Qiong
authors.initials: Q
authors.lastname: Peng
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; C526549:SF 1126; C046617:arginyl-glycyl-aspartyl-serine