耐药型Ph+白血病患者,尤其是T315I突变者目前尚无有效治疗药物。酪氨酸激酶抑制剂（TKI）类药物主要作用于Bcr/Abl激酶活性区，因此该区域的突变是造成耐药的主要原因。研究证明，阻断Bcr/Abl蛋白的多聚结构可作为治疗Ph+白血病的策略。此外Bcr/Abl能够上调MDM2的表达而抑制p53，因此激活p53蛋白也是潜在的靶点。本课题组已将Bcr/Abl蛋白四聚结构域与p53激动多肽进行了嫁接，并证实能够解决p53激动多肽递送问题。我们推测该双靶点蛋白药物，一方面可以竞争性阻断Bcr/Abl多聚结构而抑制Bcr/Abl的活性，另外一方面可以激活p53蛋白的抑癌功能，达到协同杀伤Ph+白血病细胞的目的。本项目拟通过设计合成、理化表征及在体内外验证该蛋白药物对于T315I突变Ph+白血病的抑制作用、分子机理及药效评价等临床前研究，为包括T315I在内的Ph+白血病提供新的治疗策略。

Effective treatment strategy for Tyrosine kinases inhibitors (TKIs) -resistant Philadelphia chromosome positive (Ph+) leukemia, represented by T315I muted Bcr/Abl type, remains absent and necessary. The current therapy targets kinase activity of Bcr/Abl fusion protein, thus, kinase domain mutation caused drug-resistance Ph+ leukemia stays a difficult barrier to reakthrough, despite the amount of efforts made by scientists. It has been proved that Bcr/Abl oligomerization interruption is a potential therapeutic target for Ph+ leukemia. Moreover, Bcr/Abl up-regulates the MDM2 expression level in the Ph+ leukemia cells, the p53 pathway activation is equally a potential Ph+ leukemia treatment strategy. Our research team has designed a protein drug, by engrafting the p53 activation peptide onto the Bcr/Abl oligomerization domain OLI, and by adding an amino acids sequence allowing the membrane penetration. And in our preliminary research, we have proved, at in vitro and in vivo level, that this engrafted protein drug could resolve the drug delivery problem of the p53 activation peptide. We suppose the resulting protein could play the role of dual-target protein drug, on the one hand, it could inhibit Abl kinase activity by competitively interrupting the oligomeric structure of Bcr/Abl fusion protein, on the other hand, it could activate p53 anti-cancer function, so that it could induce Ph+ leukemia cells killing by a synergic effects of the double pathways. In this project, we aim to demonstrate, via chemical synthesis and physico-chemical characterization, and in vitro, in vivo and ex vivo evaluation, the ability of engrafted protein drug to induce T315I muted Ph+ leukemia cell killing, its molecular mechanism and basic toxicity evaluation. Hopefully we could provide, for T315I muted, but not limited to T315I Ph+ leukemia, a novel candidate therapeutic strategy.