He Siyu, Liu Yang, Chu Xianglin, Li Qi, Lyu Weiping, Liu Yijun, Xing Shuaishuai, Feng Feng, Liu Wenyuan, Guo Qinglong, Zhao Li, Sun Haopeng
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People's Republic of China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
ACS Med Chem Lett. 2022 Jul 8;13(8):1286-1294. doi: 10.1021/acsmedchemlett.2c00175. eCollection 2022 Aug 11.
As a crucial target which is overexpressed in a variety of cancers, aldo-keto reductase 1C3 (AKR1C3) confers chemotherapeutic resistance to many clinical agents. However, a limited number of AKR1C3-selective inhibitors are applied clinically, which indicates the importance of identifying active compounds. Herein, we report the discovery, synthesis, and evaluation of novel and potent AKR1C3 inhibitors with structural diversity. Molecular dynamics simulations of these active compounds provide reasonable clarification of the interpreted biological data. Moreover, we demonstrate that AKR1C3 inhibitors have the potential to be superior therapeutic agents for re-sensitizing drug-resistant cell lines to chemotherapy, especially the pan-AKR1C inhibitor . Our study identifies new structural classes of AKR1C3 inhibitors and enriches the structural diversity, which facilitates the future rational design of inhibitors and structural optimization. Moreover, these compounds may serve as promising therapeutic adjuvants toward new therapeutics for countering drug resistance.
醛酮还原酶1C3（AKR1C3）作为一个在多种癌症中过度表达的关键靶点，赋予了许多临床药物化疗耐药性。然而，临床上应用的AKR1C3选择性抑制剂数量有限，这表明鉴定活性化合物的重要性。在此，我们报告了具有结构多样性的新型强效AKR1C3抑制剂的发现、合成及评价。这些活性化合物的分子动力学模拟为所解释的生物学数据提供了合理的阐释。此外，我们证明AKR1C3抑制剂有潜力成为使耐药细胞系对化疗重新敏感的优质治疗药物，尤其是泛AKR1C抑制剂。我们的研究鉴定了AKR1C3抑制剂的新结构类别并丰富了结构多样性，这有助于未来抑制剂的合理设计和结构优化。此外，这些化合物可能成为对抗耐药性新疗法的有前景的治疗佐剂。
