蛋白激酶是最重要的癌症化疗靶点，申请人对激酶靶点药物进行系列研究，成果如下：①阐明蛋白激酶BMK1经PML抑癌的机制，并以激酶组分析法筛选出BMK1抑制剂XMD8-92，改进了药筛模式(Cancer Cell,2010)；②揭示BMK1抑制剂经增强PML与MDM2互作，抑制耐药的机制(Oncogene,2013)；③阐述BMK1抑制剂经AKT调节转移的机制(Cancer Res.,2012)；④以Silac蛋白质组方法，阐明CDC25B介导雷帕霉素耐药的机制(Cancer Res.,2009)。以第一/共同第一或通讯作者在Cancer Cell等期刊上发表SCI论文8篇，单篇IF最高26.9。申请人前期发现BMK1PML控制TET2定位，调节DNA羟甲基化，因多数化疗均不同程度上需经羟甲基化，激活甲基化沉默的抑癌基因以抗肿瘤，故拟研究羟甲基化在化疗中的作用和机制，为改善化疗效果提供依据。

Protein kinases, as the major anti-cancer drug targets, play the central roles in tumorigenesis and tumor progression. Applicant is focused on the chemotherapy agents targeting protein kinases. His research accomplishments are described as follows. (1) It was described that BMK1 signaling pathway promotes tumorigenesis by the regulation of PML. Through kinome profiling, XMD8-92 was discovered as the first molecular inhibitor targeting BMK1 and verified in Xenograft as a candidate anticancer compound for chemotherapy (Cancer Cell, 2010). This inhibitor provided a new model of inhibitor discovery. (2) It was showed that BMK1 inhibitor impaired chemoresistance through disrupting the PML-MDM2 interaction (Oncogene, 2013). This work contributed to the improvement of cancer therapy. (3) It was found that BMK1 signaling pathway regulates tumor EMT through DEPTOR, which shed light on the mechanism of tumor metastasis (Cancer Res., 2012). (4) Through Silac phospho-proteomics, CDC25B was identified to play a central role in the regulation of Rapamycin-dependent induction of AKT signaling pathway (Cancer Res., 2009). Therefore CDC25B might be a suitable drug target for Rapamycin-dependent induction of AKT. To date, he has published 8 articles as first or corresponding author in SCI cited journals, such as Cancer Cell and Cancer Research, with the highest impact factor--26.9. In previous study, applicant found that BMK1-PML signaling pathway regulated the DNA 5-hydroxymethylcytosine modification through the recruitment of TET2. Considering the activity of most chemotherapy agents depends to a great extent on the activation of hypermethylated tumor suppressor through 5-hydroxymethylcytosine, applicant will study the regulation mechanism of DNA 5-hydroxymethylcytosine modification in chemotherapy, which will contribute to the improvement of chemotherapy.