Oleylamine-carbonyl-valinol inhibits auto-phosphorylation activity of native and T315I mutated Bcr-Abl, and exhibits selectivity towards oncogenic Bcr-Abl in SupB15 ALL cell lines
Oleylamine-carbonyl-valinol inhibits auto-phosphorylation activity of native and T315I mutated Bcr-Abl, and exhibits selectivity towards oncogenic Bcr-Abl in SupB15 ALL cell lines
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DOI：
10.1007/s11033-012-2282-8
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发表时间：
2013-03-01
影响因子：
2.8
通讯作者：
Mahajna, Jamal
中科院分区：
文献类型：
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作者：
Najajreh, Yousef;Khamaisie, Hazem;Mahajna, Jamal
慢性粒细胞白血病（CML）的特征是存在p210（Bcr-Abl），其表现出异常的激酶活性。选择性Abl激酶抑制剂已经成功地用于治疗CML。尽管临床应答率高，但CML患者可对这些激酶抑制剂产生耐药性，主要是由于Abl蛋白激酶结构域内的点突变。以前，我们已经确定油酸是蘑菇Daedalea gibbosa中抑制Bcr-Abl激酶活性的活性成分。（1-羟甲基-2-甲基-丙基）-3-十八碳-9-烯基-脲[油基氨基羰基-L-N-缬氨醇，油基氨基羰基-S-2-异丙基-N-乙醇胺，油胺-羰基-L-缬氨醇]（cpd 6）和R-1-（1-羟甲基-2-甲基-丙基）-3-十八碳-9-烯基-脲[油基氨基羰基-D-N-缬氨醇、油基氨基羰基-R-2-异丙基-N-乙醇胺或油基胺-羰基-D-缬氨醇]（cpd 7），Cpd 6和Cpd 7对天然Bcr-Abl和T315 I突变Bcr-Abl的活性均有抑制作用，并且在SupB 15 Ph阳性ALL细胞系中，Cpd 6和Cpd 7对致癌Bcr-Abl的活性高于天然c-Abl。
Chronic myeloid leukemia (CML) is characterized by the presence of p210(Bcr-Abl) which exhibits an abnormal kinase activity. Selective Abl kinase inhibitors have been successfully established for the treatment of CML. Despite high rates of clinical response, CML patients can develop resistance against these kinase inhibitors mainly due to point mutations within the Abl protein kinase domain. Previously, we have identified oleic acid as the active component in the mushroom Daedalea gibbosa that inhibited the kinase activity of Bcr-Abl. Here, we report that the oleyl amine derivatives, S-1-(1-Hydroxymethyl-2-methyl-propyl)-3-octadec-9-enyl-urea [oleylaminocarbonyl-L-N-valinol,oroleylaminocarbonyl-S-2-isopropyl-N-ethanolamine,oleylamine-carbonyl-L-valinol] (cpd 6) and R-1-(1-Hydroxymethyl-2-methyl-propyl)-3-octadec-9-enyl-urea [oleylamineocarbonyl-D-N-valinol, oleylaminocarbonyl-R-2-isopropyl-N-ethanolamine, or oleylamine-carbonyl-D-valinol] (cpd 7), inhibited the activity of the native and T315I mutated Bcr-Abl. Furthermore, cpd 6 and 7 exhibited higher activity towards the oncogenic Bcr-Abl in comparison to native c-Abl in SupB15 Ph-positive ALL cell line.