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

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%的急性淋巴细胞性白血病(ALL)患者是Ph+。T(9；22)导致bcr/abl融合基因的形成，该融合基因编码bcr/abl融合蛋白。与生理上的c-abl不同，c-abl的激酶活性受生长因子和其他刺激的精细调节，而bcr/abl是结构性激活的。因此，它异常地激活下游信号通路，如RAS、PI3Kinase/AKT和JAK/STAT，从而诱导白血病表型。在BCR/ABL融合蛋白中，ABL的N端部分被BCR的N端部分取代。最近，ABL的N末端(帽状区)被认为参与了ABL的激酶功能的调节。ABL的N-末端是肉豆蔻酰化的，肉豆蔻酸残基与激活域中的疏水口袋(肉豆蔻结合口袋，MBP)结合，这一过程被称为封顶。封顶将c-abl转变为自动抑制的构象。在BCR/ABL中，N端的自抑制帽区域缺失，使融合蛋白能够逃脱自身抑制。这种自我抑制的缺乏主要是导致BCR/ABL的结构性激活。基于c-ABL与肉豆蔻酸和N-末端结构域上的肉豆蔻酰基形成的配合物的晶体结构，我们提出通过肉豆蔻基模拟物竞争MBP来抑制bcr/abl的构造性激活。这些模拟物将被设计用于选择性而不是具有类似的自动抑制机制的Src家族激酶。这些竞争者将通过创新的计算机方法进行设计，合成并筛选它们在几种白血病模型中的有效性。

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.