Author: Feng, Feng ; Guo, Can ; Li, Xinyu ; Xie, Huanfang ; Shao, Jikuan ; Wang, Xiaolong ; Sun, Haopeng ; Lv, Bingbing ; Xing, Shuaishuai ; Guo, Qinglong ; Liu, Yijun

The acquired resistance of doxorubicin (DOX) significantly limits their application in breast cancer treatment. In earlier investigations, a pan-inhibitor, S07-2010, exhibiting inhibitory activity against Aldo-Keto Reductase 1C1-1C4 (AKR1C1-1C4) was discovered through virtual screening. In this study, four rounds of structural modifications were conducted, and the optimized compound 29 exhibited potent inhibitory activity against AKR1C1-1C4 (AKR1C1 IC₅₀ = 0.09 μM, AKR1C2 IC₅₀ = 0.28 μM, AKR1C3 IC₅₀ = 0.05 μM, AKR1C4 IC₅₀ = 0.51 μM). Molecular dynamics (MD) simulations revealed that 29 consistently occupied both SP2 and SP3 pockets, which may explain its pan-inhibitory activity. Utilizing highly DOX resistant MCF-7/ADR cells, 29 demonstrated superior potential as a therapeutic agent for re-sensitizing drug-resistant cell lines to chemotherapy both in vitro and in vivo, suggesting that pan-inhibition of AKR1C1-1C4 may serve as a more promising therapeutic strategy for drug-resistant breast cancer. In summary, Compound 29 may be a promising therapeutic adjuvant in the development of novel strategies to overcome drug resistance.

11 Aug 2022·ACS Medicinal Chemistry Letters

Discovery of Novel Aldo-Keto Reductase 1C3 Inhibitors as Chemotherapeutic Potentiators for Cancer Drug Resistance

Article

Author: Zhao, Li ; Liu, Wenyuan ; Lyu, Weiping ; Xing, Shuaishuai ; Sun, Haopeng ; Guo, Qinglong ; Feng, Feng ; Liu, Yang ; Li, Qi ; Liu, Yijun ; Chu, Xianglin ; He, Siyu

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 S07-2010. 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	China	China Pharmaceutical University	08 Jul 2022

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