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.

中文翻译：

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共生前药（SymProDs）双重靶向NFkappaB和CDK。

活性药物从前药中释放会产生前碎片，该前碎片通常没有生物活性，并可能导致不良反应。通过组合两种药物，其中每种药物都充当另一种药物的前碎片，将消除前药中的前碎片。由于它们互为前药并且是共生的，因此我们将它们称为共生前药（SymProDs）。为了验证这一想法，我们使用含有反应性α-亚甲基-γ-丁内酯部分的NFκB抑制剂和带有暴露在溶剂中的次级氮原子的CDK抑制剂生成了SymProD。我们显示，含有NFκB抑制剂的α-亚甲基-γ-丁内酯的仲胺前药在72小时内会缓慢释放。我们使用含有NFκB抑制剂的炔烃标记的α-亚甲基-γ-丁内酯的仲胺前药，证明了靶标的参与。在体外CDK激酶测定中，NFκB-CDKSymProD对相应的CDK抑制剂的活性低约20-200倍。在一组卵巢癌细胞系中的生长抑制研究表明，SymProD的效价趋势与单一疗法的趋势相似，表明它们在细胞中解离。总之，我们的结果表明SymProD为推进具有反应性功能的化合物提供了一条生产性途径，并可用作双重靶向剂。