A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases.
A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases.
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DOI：
10.1038/bcj.2013.63
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发表时间：
2013-11-29
影响因子：
12.8
通讯作者：
Naoe, T.
中科院分区：
文献类型：
--
作者：
Hayakawa, F.;Sugimoto, K.;Harada, Y.;Hashimoto, N.;Ohi, N.;Kurahashi, S.;Naoe, T.
信号转导和转录激活因子（STAT）蛋白是介导细胞增殖、凋亡、分化、发育和免疫应答的细胞外配体应答转录因子。STAT的异常信号诱导不受控制的细胞增殖和凋亡抵抗，并强烈参与癌症。STAT已被确定为抗肿瘤药物的一个有希望的靶标，但迄今为止大多数试验尚未成功。在这里，我们证明了一种新的STAT抑制剂OPB-31121，在没有上游激酶抑制的情况下，强烈抑制STAT3和STAT5的磷酸化，并在各种造血恶性细胞中诱导显著的生长抑制。对多种细胞系的研究表明，OPB-31121对携带BCR-ABL、FLT3/ITD和JAK2 V617F的多发性骨髓瘤、伯基特淋巴瘤和白血病特别有效，这些癌激酶的致癌性依赖于STAT3/5。利用免疫缺陷小鼠移植系统，我们发现OPB-31121对携带这些异常激酶的原发性人白血病细胞有显著的抗肿瘤作用，并且对正常人脐带血细胞具有安全性。最后，我们展示了一个模型来克服上游激酶抑制剂与STAT抑制剂的耐药性。这些结果表明OPB-31121是一种很有前景的抗肿瘤药物。一期临床试验已在韩国和香港进行，一期/二期临床试验正在日本进行。
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.
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