发现一种新型乌苯美司衍生物，作为一种首创的双重 CD13/蛋白酶体抑制剂，用于癌症治疗。
Discovery of a Novel Ubenimex Derivative as a First-in-Class Dual CD13/Proteasome Inhibitor for the Treatment of Cancer.
机构信息
College of Pharmacy, Weifang Medical University, Weifang 261053, China.
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
出版信息
Molecules. 2023 Aug 30;28(17):6343. doi: 10.3390/molecules28176343.
The CD13 inhibitor ubenimex is used as an adjuvant drug with chemotherapy for the treatment of cancer due to its function as an immunoenhancer, but it has limitations in its cytotoxic efficacy. The proteasome inhibitor ixazomib is a landmark drug in the treatment of multiple myeloma with a high anti-cancer activity. Herein, we conjugated the pharmacophore of ubenimex and the boric acid of ixazomib to obtain a dual CD13 and proteasome inhibitor (). exhibited potent inhibitory activity on both human CD13 (IC = 0.13 μM) and the 20S proteasome (IC = 1.39 μM). Although displayed lower anti-proliferative activity than that of ixazomib in vitro, an advantage was established in the in vivo anti-cancer efficacy and prolongation of survival time, which may be due to its anti-metastatic and immune-stimulating activity. A pharmacokinetic study revealed that is a potentially orally active agent with an F% value of 24.9%. Moreover, showed more favorable safety profiles than those of ixazomib in preliminary toxicity studies. Overall, the results indicate that is a promising drug candidate for the treatment of multiple myeloma.
CD13 抑制剂乌苯美司被用作化疗的辅助药物，用于治疗癌症，因为它具有免疫增强作用，但在细胞毒性方面存在局限性。蛋白酶体抑制剂伊沙佐米是治疗多发性骨髓瘤的标志性药物，具有很高的抗癌活性。在此，我们将乌苯美司的药效团和伊沙佐米的硼酸连接起来，得到一个双重 CD13 和蛋白酶体抑制剂 ()。对人 CD13（IC = 0.13 μM）和 20S 蛋白酶体（IC = 1.39 μM）均表现出很强的抑制活性。尽管在体外， 显示出比伊沙佐米更低的抗增殖活性，但在体内抗癌疗效和生存时间延长方面建立了优势，这可能是由于其具有抗转移和免疫刺激活性。药代动力学研究表明， 是一种具有潜在口服活性的药物，F%值为 24.9%。此外，在初步毒性研究中， 显示出比伊沙佐米更有利的安全性特征。总的来说，这些结果表明 是一种很有前途的治疗多发性骨髓瘤的候选药物。
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