Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.
Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.
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DOI：
10.1158/0008-5472.can-15-3062
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发表时间：
2016-08-15
期刊：
影响因子：
11.2
通讯作者：
Verma A
中科院分区：
文献类型：
--
作者：
Bachegowda L;Morrone K;Winski SL;Mantzaris I;Bartenstein M;Ramachandra N;Giricz O;Sukrithan V;Nwankwo G;Shahnaz S;Bhagat T;Bhattacharyya S;Assal A;Shastri A;Gordon-Mitchell S;Pellagatti A;Boultwood J;Schinke C;Yu Y;Guha C;Rizzi J;Garrus J;Brown S;Wollenberg L;Hogeland G;Wright D;Munson M;Rodriguez M;Gross S;Chantry D;Zou Y;Platanias L;Burgess LE;Pradhan K;Steidl U;Verma A
骨髓增生异常综合征（MDS）和急性髓性白血病（AML）抑制正常的造血活性，部分原因是骨髓中的致病性炎症环境。在本报告中，我们发现骨髓增生异常CD34+干细胞样细胞中血管生成素-1的升高与MDS和AML患者更高的疾病风险和降低的总生存率相关。血管生成素-1表达增加与已知MDS/AML干细胞样细胞特征相似的转录组特征相关。在寻找这一途径的小分子抑制剂的过程中，我们发现并验证了pexmetinib (ry -614)，一种血管生成素-1受体Tie-2的抑制剂，也被发现可以抑制促炎激酶p38 MAPK（在MDS中过度激活）。培美替尼抑制白血病增殖，阻止下游效应激酶的激活，并消除tnf - α对健康造血干细胞的影响。值得注意的是，用这种化合物治疗原发性MDS标本刺激了造血。我们的研究结果为派美替尼作为Tie-2/p38 MAPK双抑制剂用于治疗MDS/AML提供了临床前概念证明。
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34+ stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the pro-inflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases and abrogated the effects of TNF-alpha on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML.