Symbiotic Prodrugs (SymProDs) Dual Targeting of NFkappaB and CDK.

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. Since they are prodrugs of each other and are symbiotic we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFkappaB inhibitors that contain the reactive alpha-methylene-gamma-butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of alpha-methylene-gamma-butyrolactone containing NFkappaB inhibitors undergo slow release over a 72h period. Using an alkyne tagged secondary amine prodrug of alpha-methylene-gamma-butyrolactone containing NFkappaB inhibitor, we demonstrate target engagement. The NFkappaB-CDK SymProDs were ~20-200 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.