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By combining two drugs, wherein each drug acts as a pro\u2010fragment of the other drug will eliminate the pro\u2010fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NF\u03baB inhibitors that contain the reactive \u03b1\u2010methylene\u2010\u03b3\u2010butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of \u03b1\u2010methylene\u2010\u03b3\u2010butyrolactone containing NF\u03baB inhibitors undergo slow release over a 72\u00a0hr period. Using an alkyne\u2010tagged secondary amine prodrug of \u03b1\u2010methylene\u2010\u03b3\u2010butyrolactone containing NF\u03baB inhibitor, we demonstrate target engagement. The NF\u03baB\u2010CDK SymProDs were ~20\u2010 to 200\u2010fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.<\/jats:p>","DOI":"10.1111\/cbdd.13684","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T01:21:41Z","timestamp":1585704101000},"page":"773-784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK"],"prefix":"10.1111","volume":"96","author":[{"given":"Sandeep","family":"Rana","sequence":"first","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical Center Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smit","family":"Kour","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical 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