title: Synthesis and characterization of a novel prostate cancer-targeted phosphatidylinositol-3-kinase inhibitor prodrug.
abstract: The phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway is constitutively activated in a substantial proportion of prostate tumors and is considered a key mechanism supporting progression toward an androgen-independent status, for which no effective therapy is available. Therefore, PI3K inhibitors, alone or in combination with other cytotoxic drugs, could potentially be used to treat cancer with a constitutive activated PI3K/Akt pathway. To selectively target advanced prostate tumors with a constitutive activated PI3K/Akt pathway, a prostate cancer-specific PI3K inhibitor was generated by coupling the chemically modified form of the quercetin analogue LY294002 (HO-CH(2)-LY294002, compound 8) with the peptide Mu-LEHSSKLQL, in which the internal sequence HSSKLQ is a substrate for the prostate-specific antigen (PSA) protease. The result is a water-soluble and latent PI3K inhibitor prodrug (compound 11), its activation being dependent on PSA cleavage. Once activated, the L-O-CH(2)-LY294002 (compound 10) can specifically inhibit PI3K in PSA-secreting prostate cancer cells and induce apoptosis with a potency comparable to that of the original LY294002 compound.
authors.affiliation: Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Baiz
authors.forename: Tanya A
authors.initials: TA
authors.lastname: Pinder
authors.forename: Sazzad
authors.initials: S
authors.lastname: Hassan
authors.forename: Yelena
authors.initials: Y
authors.lastname: Karpova
authors.forename: Freddie
authors.initials: F
authors.lastname: Salsbury
authors.forename: Mark E
authors.initials: ME
authors.lastname: Welker
authors.forename: George
authors.initials: G
authors.lastname: Kulik
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; D017430:Prostate-Specific Antigen; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one