融合蛋白BCR-ABL的致癌作用使其成为抗肿瘤药物的理想靶标，但其激酶抑制剂存在耐药及毒副作用等问题，因此寻找新型BCR-ABL抑制剂成为目前研究的热点。前期研究表明海洋来源新骨架化合物AS1041具有显著的体内外抗肿瘤活性，它可以与BCR-ABL结合但不影响其激酶活性。进一步研究证实AS1041可以诱导BCR-ABL的泛素化降解，是一个具有全新作用机制的促BCR-ABL降解药物。本课题拟研究AS1041与BCR-ABL的相互作用及作用位点；阐明AS1041诱导BCR-ABL泛素化降解的分子机制；研究AS1041对BCR-ABL功能的抑制及其体内抗肿瘤作用与分子机制。该研究将从分子、细胞、动物水平上揭示BCR-ABL降解药物AS1041的全新作用机制，对AS1041的开发利用、设计新型的BCR-ABL降解药物具有重要意义；同时，也对发展新的BCR-ABL抑制剂提供了新的策略和理论依据。

The oncogenic fusion protein BCR-ABL has emerged as a promising target for the treatment of BCR-ABL positive tumor. However, due to the drug resistance and side effects of present tyrosine kinase inhibitors, developing novel types of inhibitors targeting BCR-ABL is very important. Our previous study has shown that compound AS1041, a marine derived anthraquinone lactone with novel skeleton, displays obvious antitumor activity both in vitro and in vivo. Further studies show that AS1041 interacts with BCR-ABL but does not affect the kinase activity of BCR-ABL. Further study reveals that AS1041 is capable of inducing the ubiquitination degradation of BCR-ABL. In the present study, we plan 1) to dissect the detailed interaction property between AS1041 and BCR-ABL, 2) to elucidate the ubiquitination degradation mechanisms of BCR-ABL induced by AS1041, 3) to study the inhibitory effect of AS1041 on BCR-ABL functions and the antitumor effect in vivo, revealing the antitumor mechanism of AS1041 in molecular, cellular, and animal level. The study is important for the drug development of AS1041. The work is of significance for elucidating the molecular mechanism of BCR-ABL degradation induced by small compounds, and provides a promising strategy for developing novel antitumor agents targeting BCR-ABL.