Synthesis and Characterization of a Novel Prostate Cancer-targeted Phosphatidylinositol-3-kinase Inhibitor Prodrug

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Aug 29

PMID 22924393

Citations 13

Authors

Daniele Baiz

Tanya A Pinder

Sazzad Hassan

Yelena Karpova

Freddie Salsbury

Mark E Welker

George Kulik

Affiliations

Soon will be listed here.

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.

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