Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.
Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.
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DOI：
10.1016/j.ejmech.2022.115013
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发表时间：
2022-12
影响因子：
6.7
通讯作者：
Yang Liu;Yuting Chen;Jiheng Jiang;Xianglin Chu;Q. Guo;L. Zhao;F. Feng;Wenyuan Liu;Xiaolong Zhang;Siyu He;P. Yang;Pengfei Fang;Haopeng Sun
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文献类型：
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作者：
Yang Liu;Yuting Chen;Jiheng Jiang;Xianglin Chu;Q. Guo;L. Zhao;F. Feng;Wenyuan Liu;Xiaolong Zhang;Siyu He;P. Yang;Pengfei Fang;Haopeng Sun
醛酮还原酶1C 3（AKR 1C 3）在多种激素相关的癌症中过表达，如乳腺癌和前列腺癌，并与肿瘤的发展和侵袭性相关。作为一种I相生物转化酶，AKR 1C 3催化导致对蒽环类药物耐药性的代谢过程，蒽环类药物是乳腺癌治疗的“金标准”。迫切需要新的方法来恢复乳腺癌的化疗敏感性。在此，我们开发了一类新的AKR 1C 3抑制剂，其表现出对密切相关的亚型的有效抑制活性和精确选择性。最佳衍生物27（S19-1035）对AKR 1C 3的IC 50值为3.04 nM，选择性是其他亚型的3289倍。我们确定了AKR 1C 3与三种抑制剂的共晶结构，为进一步基于结构的药物优化提供了坚实的基础。这些AKR 1C 3抑制剂的共同给药显著逆转了耐药乳腺癌细胞系中的多柔比星（DOX）耐药性。因此，在这项工作中开发的新型AKR 1C 3特异性抑制剂可以作为有效的佐剂来克服乳腺癌治疗中的DOX耐药性。
Aldo-keto reductase 1C3 (AKR1C3) is overexpressed in multiple hormone related cancers, such as breast and prostate cancer, and is correlated with tumor development and aggressiveness. As a phase I biotransformation enzyme, AKR1C3 catalyzes the metabolic processes that lead to resistance to anthracyclines, the “gold standard” for breast cancer treatment. Novel approaches to restore the chemotherapy sensitivity of breast cancer are urgently required. Herein, we developed a new class of AKR1C3 inhibitors that demonstrated potent inhibitory activity and exquisite selectivity for closely related isoforms. The best derivative27(S19–1035)exhibits an IC50value of 3.04 nM for AKR1C3 and >3289-fold selectivity over other isoforms. We determined the co-crystal structures of AKR1C3 with three of the inhibitors, providing a solid foundation for further structure-based drug optimization. Co-administration of these AKR1C3 inhibitors significantly reversed the doxorubicin (DOX) resistance in a resistant breast cancer cell line. Therefore, the novel AKR1C3 specific inhibitors developed in this work may serve as effective adjuvants to overcome DOX resistance in breast cancer treatment.