A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition.
A Non-ATP-Competitive Dual Inhibitor of JAK2 and BCR-ABL Kinases: Elucidation of a Novel Therapeutic Spectrum Based on Substrate Competitive Inhibition.
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DOI：
10.1177/1947601910371337
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Reddy EP
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文献类型：
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作者：
Jatiani SS;Cosenza SC;Reddy MV;Ha JH;Baker SJ;Samanta AK;Olnes MJ;Pfannes L;Sloand EM;Arlinghaus RB;Reddy EP
在这里，我们报告了ON044580的发现，这是一种α-苯甲酰苯乙烯基苯硫醚，对两种不相关的激酶JAK2和BCR-ABL具有有效的抑制活性，并且对来自慢性髓性白血病（CML）和骨髓增生异常（MDS）患者或含有JAK2激酶突变体的细胞的人类肿瘤细胞具有细胞毒性。这种新的活性谱可以用JAK2和BCR-ABL激酶的非atp竞争性抑制来解释。ON044580抑制JAK2激酶突变体和jak2v617f阳性白血病细胞的增殖，并阻断il -3介导的JAK2和STAT5的磷酸化。有趣的是，该化合物还直接抑制野生型和伊马替尼耐药（T315I）形式的BCR-ABL激酶的激酶活性。最后，ON044580有效诱导伊马替尼耐药CML患者细胞凋亡。显然不相关的JAK2和BCR-ABL激酶具有共同的底物STAT5，这种底物竞争性抑制剂代表了开发新抑制剂的另一种治疗策略。ON044580显示的激酶抑制新机制使其对突变形式的激酶如BCR-ABLT315I和JAK2V617F有效。重要的是，ON044580选择性地减少了来自单体7 MDS患者的原代骨髓样本中的非整倍体细胞的数量，这表明该药物在这些异常细胞中具有另一种调节级联作用。数据显示，该化合物可能具有多种治疗应用，包括单体7 MDS，伊马替尼耐药CML和对atp竞争药物产生耐药性的骨髓增生性肿瘤。
Here we report the discovery of ON044580, an α-benzoyl styryl benzyl sulfide that possesses potent inhibitory activity against two unrelated kinases, JAK2 and BCR-ABL, and exhibits cytotoxicity to human tumor cells derived from chronic myelogenous leukemia (CML) and myelodysplasia (MDS) patients or cells harboring a mutant JAK2 kinase. This novel spectrum of activity is explained by the non–ATP-competitive inhibition of JAK2 and BCR-ABL kinases. ON044580 inhibits mutant JAK2 kinase and the proliferation of JAK2V617F-positive leukemic cells and blocks the IL-3–mediated phosphorylation of JAK2 and STAT5. Interestingly, this compound also directly inhibits the kinase activity of both wild-type and imatinib-resistant (T315I) forms of the BCR-ABL kinase. Finally, ON044580 effectively induces apoptosis of imatinib-resistant CML patient cells. The apparently unrelated JAK2 and BCR-ABL kinases share a common substrate, STAT5, and such substrate competitive inhibitors represent an alternative therapeutic strategy for development of new inhibitors. The novel mechanism of kinase inhibition exhibited by ON044580 renders it effective against mutant forms of kinases such as the BCR-ABLT315I and JAK2V617F. Importantly, ON044580 selectively reduces the number of aneuploid cells in primary bone marrow samples from monosomy 7 MDS patients, suggesting another regulatory cascade amenable to this agent in these aberrant cells. Data presented suggest that this compound could have multiple therapeutic applications including monosomy 7 MDS, imatinib-resistant CML, and myeloproliferative neoplasms that develop resistance to ATP-competitive agents.