{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:42:21Z","timestamp":1790959341689,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,2,2]],"date-time":"2016-02-02T00:00:00Z","timestamp":1454371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Mass Spectrometry Core at Johns Hopkins","award":["P30 CA006973"],"award-info":[{"award-number":["P30 CA006973"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>There is an urgent need to develop new agents for treating metastatic prostate cancer to overcome multiple drug resistance to the current standard targeted cancer therapy. Emetine is a highly cytotoxic natural product protein synthesis inhibitor, which is toxic to all cell types. Its cytotoxicity can be blocked by derivatizing its N\u20102\u2032 position. Thus emetine can be selectively delivered to cancer cells in the region of metastatic cancer as a prodrug that will be activated by an enzyme selectively overexpressed within the metastatic tumor microenvironment. In this work, we convert emetine to a prodrug activatable by the fibroblast activation protein (FAP), a serine protease overexpressed by the carcinoma associated fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHOD<\/jats:title><jats:p>By using an iterative structure\u2010activity relationship strategy, several peptidyl emetine prodrug analogs (<jats:bold>1\u201311<\/jats:bold>) were synthesized by chemical derivatization of emetine at its N\u20102\u2032 position and tested for in\u2010vitro activation by FAP. The lead prodrug <jats:bold>11<\/jats:bold> is made up of a DPPIV activatable prodrug precursor <jats:bold>10<\/jats:bold> (Ala\u2010Pro\u2010PABC\u2010Emetine) coupled to FAP substrate (Ala\u2010Ser\u2010Gly\u2010Pro\u2010Ala\u2010Gly\u2010Pro). Activation assays of the prodrugs were performed in purified FAP, DPPIV, FBS, and human serum and were analyzed by LCMS. In vitro cytotoxicity assays of these prodrugs are carried out in prostate (LNCaP, PC3) and breast (MCF7 and MDA\u2010MB\u2010231) cancer cell lines. The prodrugs are also tested in normal immortalized human prostatic epithelial cell line (PrEC).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>The lead FAP activated emetine prodrug <jats:bold>11<\/jats:bold> is activated to emetine in tandem by FAP and DPPIV in about 70% conversion within 24\u2009hr. In prostate and breast cancer cell lines treated with prodrug <jats:bold>11<\/jats:bold>, it is found to be equipotent with emetine in the presence of FAP and DPPIV. However, in the PrEC cell line grown in serum free media, prodrug <jats:bold>11<\/jats:bold> is more than 200\u2010fold less cytotoxic than emetine in the absence of FAP and DPPIV.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>This FAP activated prodrug of cytotoxic agent emetine further shows the crucial role of the N\u20102\u2032 position of emetine in controlling its cytotoxicity. Significantly reduced toxicity observed in the PrEC cell line in the absence of FAP and DPPIV shows that prodrug <jats:bold>11<\/jats:bold> could be systemically delivered to regions of metastatic prostate cancer or other solid tumor for activation by cancer selective enzymes within the cancer microenvironment, such as FAP that is overexpressed by the carcinoma\u2010associated fibroblasts. The two\u2010step tandem enzymatic activation of prodrug <jats:bold>11<\/jats:bold> by FAP and DPPIV is a strategy for overcoming steric hindrance. <jats:italic>Prostate 76:703\u2013714, 2016<\/jats:italic>. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pros.23162","type":"journal-article","created":{"date-parts":[[2016,2,2]],"date-time":"2016-02-02T13:38:57Z","timestamp":1454420337000},"page":"703-714","source":"Crossref","is-referenced-by-count":27,"title":["Iterative design of emetine\u2010based prodrug targeting fibroblast activation protein (FAP) and dipeptidyl peptidase IV DPPIV using a tandem enzymatic activation strategy"],"prefix":"10.1002","volume":"76","author":[{"given":"Emmanuel S.","family":"Akinboye","sequence":"first","affiliation":[{"name":"Department of Oncology Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Nathaniel","family":"Brennen","sequence":"additional","affiliation":[{"name":"Department of Oncology Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Marc","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Oncology Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oladapo","family":"Bakare","sequence":"additional","affiliation":[{"name":"Department of Chemistry Howard University District of Columbia Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel R.","family":"Denmeade","sequence":"additional","affiliation":[{"name":"Department of Oncology Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Johns Hopkins University School of Medicine Baltimore 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