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首页> 外文期刊>British Journal of Haematology >Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma.
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Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma.

机译：新型多酪氨酸激酶和极光激酶抑制剂ENMD-2076对多发性骨髓瘤的临床前活性。

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摘要

ENMD-2076 is a novel, orally-active molecule that has been shown to have significant activity against aurora and multiple receptor tyrosine kinases. We investigated the activity of ENMD-2076 against multiple myeloma (MM) cells in vitro and in vivo. ENMD-2076 showed significant cytotoxicity against MM cell lines and primary cells, with minimal cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibited the phosphoinositide 3-kinase/AKT pathway and downregulated survivin and X-linked inhibitor of apoptosis as early as 6 h after treatment. With longer treatment (24-48 h), ENMD-2076 also inhibited aurora A and B kinases, and induced G(2)/M cell cycle arrest. In non-obese diabetic/severe combined immunodeficient mice implanted with H929 human plasmacytoma xenografts, oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) resulted in a dose-dependent inhibition of tumour growth. Immunohistochemical staining of excised tumours showed significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3 at all dose levels compared to tumours from vehicle-treated mice. In addition, a significant reduction in p-FGFR3 was observed on Western blot. ENMD-2076 shows significant activity against MM cells in vitro and in vivo, and acts on several pathways important for myeloma cell growth and survival. These results provide preclinical rationale for clinical investigation of ENMD-2076 in MM.
机译：ENMD-2076是一种新型的口服活性分子，已显示出对极光和多种受体酪氨酸激酶的显着活性。我们在体外和体内研究了ENMD-2076对多发性骨髓瘤（MM）细胞的活性。 ENMD-2076对MM细胞系和原代细胞显示出显着的细胞毒性，对造血祖细胞的细胞毒性最小。 ENMD-2076最早在治疗后6小时就抑制了磷酸肌醇3-激酶/ AKT通路，并下调了survivin和X连锁的凋亡抑制剂。经过更长的治疗（24-48小时），ENMD-2076还抑制了极光A和B激酶，并诱导了G（2）/ M细胞周期停滞。在植入了H929人浆细胞瘤异种移植物的非肥胖糖尿病/重度合并免疫缺陷小鼠中，口服ENMD-2076（每天50、100、200 mg / kg）可导致剂量依赖性抑制肿瘤生长。与来自媒介物治疗的小鼠的肿瘤相比，切除的肿瘤的免疫组织化学染色显示磷酸组蛋白3（pH3），Ki-67和血管生成显着减少，裂解的caspase-3在所有剂量水平上也显着增加。另外，在蛋白质印迹上观察到p-FGFR3的显着降低。 ENMD-2076在体外和体内均显示出对MM细胞的显着活性，并在对骨髓瘤细胞生长和存活至关重要的几种途径中起作用。这些结果为ENMD-2076在MM中的临床研究提供了临床前依据。

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