Design, Synthesis, and Screening of Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitors Activated by Prostate Specific Antigen (PSA): Prodrug Treatment for Androgen-Independent Prostate Cancer

Abstract

The PI3K/Akt pathway is one of the most frequently dysregulated signaling pathways in cancer and remains a crucial target in drug development. Current therapeutic drugs are potent, but often lack the cellular specificity needed to lower toxicity effects. Here we show the design and synthesis of two types of novel PSA-activated PI3K inhibitors for the treatment of androgen-independent prostate cancer. Both literature and predictive molecular modeling studies suggest PI3K enzyme inhibition in the nanomolar/picomolar range. Type I PI3K inhibitors contain: (1) a pyrimidine or triazine core, (2) a secondary amine - usually a morpholine ring, and (3) an aromatic/heteroaromatic group capable of hydrogen bonding. Type II PI3K inhibitors contain these same three moieties but with added electrophilic functional groups or electron withdrawing groups (EWG) on the secondary amine and the aromatic/heteroaromatic group. These functional groups will allow reversible covalent bond forming reactions to occur with nucleophilic amino acids in the active site of PI3K - an approach that has not been attempted. Reversible covalent bond forming reactions are hypothesized to allow the inhibitor to stay in the active site longer and thus enhance its potency towards the targeted enzyme. Additionally, the attachment of a peptide chain, with the embedded amino acid sequence HSSKLQ recognized and cleaved by prostate specific antigen (PSA), to both Type I and Type II PI3K inhibitors, is hypothesized to significantly improve specificity towards prostate cells (based off our previously published work) and subsequently: (1) prevent further cellular proliferation of prostate cancer cells, (2) lower toxicity effects, and (3) induce apoptosis through Caspase activity. Testing our active Type I and Type II PI3K inhibitors via western blot analysis against the current clinical trial PI3K inhibitor ZSTK474 showed 10-fold to 100-fold improvement in inhibition.