文章：

一种新的STAT抑制剂OPB-31121对STAT成瘾的肿瘤激酶白血病具有显著的抗肿瘤作用

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

原文发布日期：2013-11-29

DOI: 10.1038/bcj.2013.63

类型: Original Article

开放获取: 是

英文摘要：

Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR–ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan.

摘要翻译： 

信号转导与转录激活因子（STAT）蛋白是细胞外配体响应性转录因子，介导细胞增殖、凋亡、分化、发育及免疫应答。STAT的异常信号传导会诱发不受控的细胞增殖与抗凋亡效应，并与癌症发生密切相关。STAT已被确定为抗肿瘤药物的潜在作用靶点，但迄今为止大多数临床试验尚未取得成功。本研究证实，新型STAT抑制剂OPB-31121在不抑制上游激酶的情况下，能强力阻断STAT3和STAT5的磷酸化，并在多种造血系统恶性肿瘤细胞中诱导显著生长抑制。通过多种细胞系实验发现，OPB-31121对多发性骨髓瘤、伯基特淋巴瘤及携带BCR-ABL、FLT3/ITD和JAK2 V617F（其致癌性依赖于STAT3/5的癌激酶）的白血病具有显著疗效。采用免疫缺陷小鼠移植模型，我们证实OPB-31121对携带这些异常激酶的原代人白血病细胞具有显著抗肿瘤效果，且对正常人脐血细胞安全性良好。最后，我们构建了STAT抑制剂克服上游激酶抑制剂耐药性的模型。这些结果表明OPB-31121是一种前景广阔的靶向抗肿瘤药物。该药物已在韩国和香港完成I期临床试验，目前在日本正在进行I/II期试验。

原文链接：

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases