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Targeting the Myristoyl Binding Pocket in BCR/ABL: A Rational Approach for the Design of Molecular Therapy Against Philadelphia Chromosome-Positive Leukemia

靶向 BCR/ABL 中的肉豆蔻酰结合袋：费城染色体阳性白血病分子治疗设计的合理方法

基本信息

批准号：
30388368
负责人：
Privatdozent Dr. Martin Ruthardt
金额：
--
依托单位：
Faculty of Pharmacy
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2006
资助国家：
德国
起止时间：
2005-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/30388368?language=en
关键词：
Targeting Myristoyl Binding Pocket BCR

项目摘要

The cytogenetic correlate of the t(9;22) is the Philadelphia chromosome. 95% of patients suffering from chronic myeloid leukemia (CML) and 25-30% of patient with acute lymphatic leukemia (ALL) are Philadelphia chromosome-positive (Ph+). The t(9;22) leads to the formation of the chimeric bcr/abl fusion gene which encodes for the BCR/ABL fusion protein. In contrast to its physiological counterpart c-ABL, whose kinase activity is finely regulated by growth factors and other stimuli, BCR/ABL is constitutively activated. Thus it aberrantly activates down-stream signaling pathways such as RAS, PI3 Kinase/AKT as well as JAK/STAT inducing the leukemic phenotype. In the BCR/ABL fusion protein, the N-terminus part of ABL is replaced with the N-terminus part of BCR. Recently, the N-terminus end (Cap region) of ABL was implicated in regulating the kinase function of ABL. The N-terminus of ABL is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain (Myristoyl binding pocket, MBP), a process called capping . The capping turns c-ABL into an auto-inhibited conformation. The N-terminal auto-inhibitory Cap region is absent in the BCR/ABL allowing the fusion protein to escape the autoinhibition. This lack of auto-inhibition mainly contributes to the constitutive activation of BCR/ABL. Based on the crystal structure of c-ABL in complex with myristic acid and with myristoyl from the N-terminal domain we propose to inhibit the constitutive activation of BCR/ABL by myristoyl mimics which compete for the MBP. These mimics will be designed for selectivity versus Src family kinases which could have a similar mechanism of auto-inhibition. Such competitors will be designed by innovative computer methods, synthesized and screened for their efficacy in several leukemia models.

t（9;22）的细胞遗传学相关是费城染色体。95%的慢性粒细胞白血病（CML）患者和25-30%的急性淋巴细胞白血病（ALL）患者是费城染色体阳性（Ph+）。t（9;22）导致编码BCR/ABL融合蛋白的嵌合bcr/abl融合基因的形成。与其生理对应物c-ABL（其激酶活性受生长因子和其他刺激物精细调节）相反，BCR/ABL是组成性激活的。因此，它异常激活下游信号通路，如RAS，PI 3激酶/AKT以及JAK/STAT诱导白血病表型。在BCR/ABL融合蛋白中，ABL的N-末端部分被BCR的N-末端部分替换。最近，ABL的N-末端（帽区）涉及调节ABL的激酶功能。ABL的N-末端被肉豆蔻酰化，并且肉豆蔻酸残基结合到激酶结构域中的疏水口袋（肉豆蔻酰结合口袋，MBP），该过程称为帽化。加帽将c-ABL转变为自抑制构象。BCR/ABL中不存在N-末端自抑制帽区，从而允许融合蛋白逃避自抑制。基于c-ABL与肉豆蔻酸和N-末端结构域的肉豆蔻酰复合物的晶体结构，我们提出通过竞争MBP的肉豆蔻酰模拟物来抑制BCR/ABL的组成性激活。这些模拟物将被设计用于相对于Src家族激酶的选择性，Src家族激酶可能具有类似的自抑制机制。这些竞争者将通过创新的计算机方法设计，合成并在几种白血病模型中筛选其疗效。