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-CH2-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-CH2-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.
Written by:
Baiz D, Pinder TA, Hassan S, Karpova Y, Salsbury F, Welker ME, Kulik G. Are you the author?
Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine , Medical Center Boulevard, Winston-Salem, North Carolina 27157, United States.
Reference: J Med Chem. 2012 Sep 27;55(18):8038-46.
doi: 10.1021/jm300881a
PubMed Abstract
PMID: 22924393
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