Colchicine Binding Site Agent DJ95 Overcomes Drug Resistance and Exhibits Antitumor Efficacy
Colchicine Binding Site Agent DJ95 Overcomes Drug Resistance and Exhibits Antitumor Efficacy
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秋水仙碱结合位点剂DJ95克服耐药性并表现出抗肿瘤功效
DOI：
10.1124/mol.118.114801
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发表时间：
2019-07-01
影响因子：
3.6
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Arnst, Kinsie E.;Wang, Yuxi;Li, Wei
干扰微管动力学是一种行之有效的癌症治疗策略；然而，许多微管靶向药物与耐药和不良反应有关。大量证据表明，atp结合盒（ABC）转运体在耐药性的发展中起着关键作用。在此，我们证明了DJ95 （2-（1h -吲哚-6-基）-4-（3,4,5-三甲氧基苯基）- 1h -咪唑[4,5-c]吡啶），一种新型微管蛋白抑制剂，对多种癌细胞系的疗效，包括恶性黑色素瘤，药物选择耐药细胞系，特异性ABC转运蛋白过表达细胞系，以及国家癌症研究所60细胞系面板。DJ95抑制了癌细胞的迁移，引起微管网络基础的形态学改变，严重破坏了有丝分裂细胞的纺锤体形成。DJ95与微管蛋白复合物的高分辨率晶体结构和详细的分子相互作用证实了其直接结合秋水仙碱位点。使用SafetyScreen44 （Eurofins Cerep-Panlabs）对DJ95进行体外药理学筛选，发现无明显的脱靶相互作用，药代动力学分析显示，DJ95在小鼠体内维持治疗相关的血浆浓度长达24小时。在裸鼠A375异种移植瘤模型中，DJ95抑制肿瘤生长，破坏肿瘤血管。这些结果表明，DJ95对多种细胞系有效，对ABC转运蛋白过表达的细胞系的效力比现有的微管蛋白抑制剂更强，直接靶向秋水仙碱结合结构域，具有显著的抗肿瘤功效，并具有血管破坏特性。总的来说，这些数据表明DJ95作为一种癌症治疗药物具有巨大的潜力，特别是对于多药耐药表型，值得进一步开发。紫杉醇是一种广泛应用于肿瘤治疗的微管蛋白抑制剂，但其临床疗效往往受到多药耐药的限制。在这项研究中，我们报道了一种新的微管蛋白抑制剂DJ95的临床前特征，并证明了它能够克服紫杉醇耐药，破坏肿瘤血管，并表现出显著的抗肿瘤功效。
Interfering with microtubule dynamics is a well-established strategy in cancer treatment; however, many microtubule-targeting agents are associated with drug resistance and adverse effects. Substantial evidence points to ATP-binding cassette (ABC) transporters as critical players in the development of resistance. Herein, we demonstrate the efficacy of DJ95 (2-(1H-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine), a novel tubulin inhibitor, in a variety of cancer cell lines, including malignant melanomas, drug-selected resistant cell lines, specific ABC transporter–overexpressing cell lines, and the National Cancer Institute 60 cell line panel. DJ95 treatment inhibited cancer cell migration, caused morphologic changes to the microtubule network foundation, and severely disrupted mitotic spindle formation of mitotic cells. The high-resolution crystal structure of DJ95 in complex with tubulin protein and the detailed molecular interactions confirmed its direct binding to the colchicine site. In vitro pharmacological screening of DJ95 using SafetyScreen44 (Eurofins Cerep-Panlabs) revealed no significant off-target interactions, and pharmacokinetic analysis showed that DJ95 was maintained at therapeutically relevant plasma concentrations for up to 24 hours in mice. In an A375 xenograft model in nude mice, DJ95 inhibited tumor growth and disrupted tumor vasculature in xenograft tumors. These results demonstrate that DJ95 is potent against a variety of cell lines, demonstrated greater potency to ABC transporter–overexpressing cell lines than existing tubulin inhibitors, directly targets the colchicine binding domain, exhibits significant antitumor efficacy, and demonstrates vascular-disrupting properties. Collectively, these data suggest that DJ95 has great potential as a cancer therapeutic, particularly for multidrug resistance phenotypes, and warrants further development. Significance Statement Paclitaxel is a widely used tubulin inhibitor for cancer therapy, but its clinical efficacy is often limited by the development of multidrug resistance. In this study, we reported the preclinical characterization of a new tubulin inhibitor DJ95, and demonstrated its abilities to overcome paclitaxel resistance, disrupt tumor vasculature, and exhibit significant antitumor efficacy.