Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK.

Autor: Rana S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Kour S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Sonawane YA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Robb CM; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Contreras JI; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Kizhake S; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA., Zahid M; Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE, USA., Karpf AR; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA., Natarajan A; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.; Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
Jazyk: angličtina
Zdroj: Chemical biology & drug design [Chem Biol Drug Des] 2020 Aug; Vol. 96 (2), pp. 773-784. Date of Electronic Publication: 2020 Apr 22.
DOI: 10.1111/cbdd.13684
Abstrakt: The release of an active drug from the prodrug generates a pro-fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro-fragment of the other drug will eliminate the pro-fragment 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 NFκB inhibitors that contain the reactive α-methylene-γ-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α-methylene-γ-butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne-tagged secondary amine prodrug of α-methylene-γ-butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB-CDK SymProDs were ~20- to 200-fold 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.
(© 2020 John Wiley & Sons A/S.)
Databáze: MEDLINE
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