针对伊马替尼耐药慢性粒细胞白血病的新靶点确证

BCR-ABL是费城染色体阳性慢性粒细胞白血病（Ph+-CML）的原凶。靶向BCR-ABL酪氨酸激酶抑制剂（TKI）带来了肿瘤治疗的革命性进展。作为首个TKI，伊马替尼对Ph+-CML病人有效，但临床耐药问题日益严重。虽然第二和第三代TKI能部分对抗突变引起的耐药，但目前尚无根本解决办法。本课题组前期发现苯氧基嘧啶化合物TGI1003对酪氨酸激酶无抑制作用，却能有效抑制耐药CML细胞的增殖，提示其抗耐药作用的靶点和机制与TKI完全不同。采用化学蛋白质组学技术捕获了其特异结合蛋白SET，并初步证明通过抑制SET-PP2A相互作用而发挥功能。本课题将通过探讨TGI1003与SET特异结合的模式、解析二者相互作用的结构基础、研究下游信号转导网络及调控、设计和考察SET小分子抑制剂以验证靶点的可靠性，阐明TGI1003对抗伊马替尼耐药的靶点和机制，为解决Ph+-CML耐药问题提供新的策略和手段。

Bcr-Abl is the cause for Philadelphia chromosome-positive chronic myelocytic leukemia (Ph+-CML). The development of Tyrosine kinase inhibitor (TKI) has been a breakthrough in cancer therapy. As the first TKI, Imatinib is effective in Ph+-CML patients, but drug resistance has become a major issue in clinical applications. Although the second and third generations of TKI can partially be effective against the drug resistance from gene mutations, it remains fundamentally challenging to completely resolve the resistance issue. We found that a pheyloxypyrimidine compound TGI1003 can effectively inhibit the proliferation of Ph+-CML cells without inhibition on kinase activity, suggesting that the target and mechanism for this compound is completely different from TKI. Subsequently, we obtained a specific binding protein SET by chemical proteomics approach, and the effects of TGI1003 were mediated by inhibiting SET-PP2A interaction. In the present study, we will elucidate and validate the target and mechanism for TGI1003 on the inhibition of Ph+-CML by the investigations of the interaction between TGI1003 and SET, the structural basis of the interaction, downstream signaling process and regulation and design and examination of small molecule SET inhibitors for further confirmation., which will provide a new strategy and effective tools to fight TKI-resistant Ph+-CML.