Design and synthesis of alpha-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation
Design and synthesis of alpha-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation
复制标题
α-萘黄酮嵌合体衍生物的设计和合成能够通过靶向 CYP1B1 降解消除细胞色素 P450 (CYP)1B1 介导的耐药性
DOI：
10.1016/j.ejmech.2019.112028
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发表时间：
2020
影响因子：
6.7
通讯作者：
Zhou Wen
中科院分区：
文献类型：
--
作者：
Zhou Li;Chen Wenming;Cao Chenyang;Shi Yonghui;Ye Wenchong;Hu Jiliang;Wang LingLi;Zhou Wen
肝外细胞色素P450 1B 1（Extrahepatic cytochrome P450 1B 1，CYP 1B 1）在多种肿瘤中高度表达，是一个极具吸引力和潜在的肿瘤预防、治疗和逆转耐药的靶点。抑制CYP 1B 1是目前治疗CYP 1B 1介导的恶性肿瘤的主要治疗模式，但治疗效果不佳。在此，我们报告了CYP 1B 1降解代替CYP 1B 1抑制，使用PROTAC策略逆转CYP 1B 1过表达前列腺癌细胞系DU 145对多西他赛的耐药性。用乙炔基取代我们以前发现的一种CYP 1B 1选择性抑制剂的氯原子，得到了对CYP 1B 1保持强抑制（IC 50 = 0.4 ± 0.2 nM）和高选择性的α-萘啶酮衍生物5。将5与不同链长的沙利度胺衍生物偶联，得到偶联物6A-Dviaclick反应，体外细胞实验表明，6C对CYP 1B 1高表达的DU 145细胞的耐药性有较好的消除作用。Western blotting分析表明，CYP 1B 1降解是逆转多西他赛耐药性的主要原因之一，且呈浓度依赖性。本研究首次尝试通过降解CYP 1B 1而不是抑制CYP 1B 1来克服CYP 1B 1介导的耐药性，为消除耐药性提供了新的方向。
Extrahepatic cytochrome P450 1B1 (CYP1B1), which is highly expressed in various tumors, is an attractive and potential target for cancer prevention, therapy, and reversal of drug resistance. CYP1B1 inhibition is the current predominant therapeutic paradigm to treating CYP1B1-mediated malignancy, but therapeutic effect has little success. Herein, we reported CYP1B1 degradation in place of CYP1B1 inhibition for reversing drug resistance toward docetaxel in CYP1B1-overexpressing prostate cancer cell line DU145 using a PROTAC strategy. Replacing chlorine atom of a CYP1B1 selective inhibitor we found previously with ethynyl, we got the resulting α-naphthoflavone derivative5which kept strong inhibition against CYP1B1 (IC50= 0.4 ± 0.2 nM) and high selectivity. Coupling of5with thalidomide derivatives of varying chain lengths afforded conjugates6A-Dviaclick reaction.In vitrocell-based assay indicated that6Cwas more effective in eliminating drug resistance of CYP1B1-overexpressed DU145 cells compared with other analogues. Western blotting analysis showed CYP1B1 degradation was one main reason for the reversal of drug resistance to docetaxel and the effect was obtained in a concentration-dependent manner. This work is the first attempt to overcome CYP1B1-mediated drug resistanceviaCYP1B1 degradation instead of CYP1B1 inhibition, which could provide a new direction toward eliminating drug resistance.