ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action
ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action
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DOI：
10.1158/1535-7163.mct-10-0574
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发表时间：
2011-01-01
影响因子：
5.7
通讯作者：
Bray, Mark R.
中科院分区：
文献类型：
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作者：
Fletcher, Graham C.;Brokx, Richard D.;Bray, Mark R.
ENMD-2076是一种新型的口服活性小分子激酶抑制剂，其作用机制涉及几个对肿瘤生长和生存至关重要的途径：血管生成、增殖和细胞周期。ENMD-2076对有丝分裂激酶Aurora A以及参与血管生成的激酶(VEGFRs，FGFRs)具有选择性活性。ENMD-2076在体外对多种人实体瘤和造血癌细胞系的生长有抑制作用，IC50值在0.025~0.7mU/L之间。在乳腺癌、结肠癌、黑色素瘤、白血病和多发性骨髓瘤细胞系的异种移植模型中，ENMD-2076在耐受性良好的剂量下也能诱导体内肿瘤的消退或完全抑制。体内药效学实验表明，除抑制Aurora A外，单次剂量的ENMD-2076对Flt3的激活以及血管生成酪氨酸激酶VEGFR2/KDR和FGFR1和2均有持续的抑制作用。ENMD-2076可防止体内新生血管的形成和使已形成的血管退化，其剂量相当于在异种肿瘤模型中具有实质性活性的剂量。这些结果表明，ENMD-2076是一种耐受性良好的口服活性多靶点激酶抑制剂，具有独特的抗血管生成/抗增殖特性，并为用于治疗人类癌症提供了强有力的临床前支持。涉及ENMD-2076的几项第一阶段研究最近已经完成，该化合物目前正在对对铂耐药的卵巢癌患者进行第二阶段临床试验。摩尔癌症治疗；10(1)；126-37。(C)2010年AACR。
ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 values ranging from 0.025 to 0.7 mu mol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer. Mol Cancer Ther; 10(1); 126-37. (C)2010 AACR.