人源组成型雄烷受体激动剂 DL5016：一种新型增敏剂，可增强基于环磷酰胺的化疗药物疗效。
Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies.
机构信息
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, 21201, United States.
9800 Medical Center Drive, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, United States.
出版信息
Eur J Med Chem. 2019 Oct 1;179:84-99. doi: 10.1016/j.ejmech.2019.06.031. Epub 2019 Jun 15.
The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC value of 0.66 μM and E value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells.
DNA 烷化剂前体药物环磷酰胺（CPA），单独或与其他药物联合使用，是最常用的抗癌药物之一。作为前体药物，CPA 由细胞色素 P450 2B6（CYP2B6）激活，后者受人体组成型雄烷受体（hCAR）转录调控。因此，hCAR 激动剂代表了基于 CPA 的治疗的新型增敏剂。在已知的 hCAR 激动剂中，6-（4-氯苯基）咪唑并[2,1-b]噻唑-5-甲酰醛-O-（3,4-二氯苄基）肟（CITCO）是最有效和广泛应用于生物学研究的一种。通过对 CITCO 的结构修饰，我们开发了一种新型化合物 DL5016（32），它在激活 hCAR 时的 EC 值为 0.66 μM，E 值为 4.9。DL5016 可显著诱导 hCAR 靶基因 CYP2B6 的表达，无论是在 mRNA 水平还是在蛋白水平，并导致 hCAR 从人原代肝细胞的细胞质向细胞核易位。DL5016 增强了基于 CPA 的细胞毒性对非霍奇金淋巴瘤细胞的疗效，突出了其作用。
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