title: Development of inhibitor-directed enzyme prodrug therapy (IDEPT) for prostate cancer.
abstract: Prostate cancer (PCa) is the second most common cause of cancer death among American men after lung cancer. Unfortunately, current therapies do not provide effective treatments for patients with advanced, metastatic, or hormone refractory disease. Therefore, we seek to generate therapeutic agents for a novel PCa treatment strategy by delivering a suicide enzyme (yCDtriple) to a cell membrane bound biomarker found on PCa cells (prostate-specific membrane antigen (PSMA)). This approach has resulted in a new PCa treatment strategy reported here as inhibitor-directed enzyme prodrug therapy (IDEPT). The therapeutic agents described were generated using a click chemistry reaction between the unnatural amino acid (p-azidophenylalanine (pAzF)) incorporated into yCDtriple and the dibenzylcyclooctyne moiety of our PSMA targeting agent (DBCO-PEG4-AH2-TG97). After characterization of the therapeutic agents, we demonstrate significant PCa cell killing of PSMA-positive cells. Importantly, we demonstrate that this click chemistry approach can be used to efficiently couple a therapeutic protein to a targeting agent and may be applicable to the ablation of other types of cancers and/or malignancies.
authors.affiliation: School of Molecular Biosciences and §Department of Chemistry, Washington State University , Pullman, Washington 99164-7520, United States.
authors.forename: Stacy E
authors.initials: SE
authors.lastname: Martin
authors.forename: Tanushree
authors.initials: T
authors.lastname: Ganguly
authors.forename: Gerhard R
authors.initials: GR
authors.lastname: Munske
authors.forename: Melody D
authors.initials: MD
authors.lastname: Fulton
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hopkins
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Black
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001386:Azides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057930:Click Chemistry; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D001386:Azides; D011355:Prodrugs; C027162:4-azidophenylalanine; D010649:Phenylalanine; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II