Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer
Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer
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DOI：
10.1021/acs.jmedchem.0c00939
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发表时间：
2020-09-24
影响因子：
7.3
通讯作者：
Ikari, Akira
中科院分区：
文献类型：
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作者：
Endo, Satoshi;Oguri, Hiroaki;Ikari, Akira
醛酮还原酶（AKR）1C 3催化活性雄激素的合成，促进前列腺癌的进展。AKR 1C 3还通过代谢拟南芥素和反应性醛来促进雄激素非依赖性细胞增殖和存活。由于其在去势抵抗性前列腺癌（CRPC）组织中的升高，AKR 1C 3是CRPC的有希望的治疗靶点。在这项研究中，我们发现了一种新的有效的AKR 1C 3抑制剂，N-（4-氟苯基）-8-羟基-2-亚氨基-2H-色烯-3-甲酰胺（2d），并合成了其衍生物，其IC 50值为25-56 nM，选择性超过其他AKR（1C 1，1C 2和1C 4）220倍。通过晶体学研究AKR 1C 3与2 j和2l的复合物，阐明了抑制效力的结构因素。抑制剂通过雄激素依赖性和雄激素非依赖性机制抑制前列腺癌22 Rv 1和PC 3细胞的增殖。另外，2 j和2l防止异种移植小鼠模型中的前列腺肿瘤生长。此外，抑制剂显著增加了抗CRPC药物（阿比特龙或恩杂鲁胺）诱导的凋亡性细胞死亡。
Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).