基于Bcr-Abl(T315I)为靶标的新型酪氨酸激酶抑制剂的设计、合成与活性研究

Bcr-Abl酪氨酸激酶是慢性粒细胞白血病的主要诱因，针对该靶标已有多种药物上市，但耐药问题亦随之而来，尤其是T315I点突变产生的耐药性是临床上亟待解决的问题。本课题以Bcr-Abl(T315I)为靶标，采用基于片段的药物设计策略，开展新型小分子酪氨酸激酶抑制剂的设计、合成与生物活性研究。在前期发现的柔性Linker可行性基础上，借鉴肿瘤代谢组学的发现，根据六原子限定原则，在Linker部分引入氨基酸，与杂环联苯等铰链区结合基团进行原位装配，拟设计合成三个系列Bcr-Abl抑制剂，进而开展分子水平及细胞水平的活性研究，并进行构效关系分析，在此基础上开展新一轮的结构优化和体内外抗肿瘤活性研究。本项目的开展，可丰富Bcr-Abl(T315I)抑制剂的结构类型，为最终发现结构新颖的高效、低毒的Bcr-Abl(T315I)抑制剂抗肿瘤候选药物奠定基础。

Bcr-Abl tyrosine kinase, encoding by BCR-ABL oncogene, can drive chronic myeloid leukemia (CML) through phosphorylation of many downstream effector molecules. Due to non-expression of Bcr-Abl kinase in the normal hemopoietic stem cell, it is a well validated target for the treatment of CML. Although many Bcr-Abl inhibitors have been approved, acquired resistance remians a major challenge for clinical management of CML, especially T315I mutation-induced drug resistance. In our previous study, the novel Bcr-Abl inhibitors bearing diacylated piperazine as flexible linker were designed and synthesized. The biological evaluation indicated that the incorporation of flexible Linker into Bcr-Abl inhibitors was feasible. In recent years, metabonomics research suggested that tumor tissues needed more amino acids than normal tissues. Therefore, introducing amino acid into antitumor agents can improve the selectivity for tumor cells. Based on above findings, amino acids will be incorporated as novel Linker under the regulation of six-atom. Using fragment-based drug design, combined with various hinge binding moieties, three series of Bcr-Abl(T315I) inhibitors will be synthesized, and characterized by NMR and MS. The biological activities of target compounds will be evaluated against Bcr-Abl (WT and T315I), malignant cell lines (K562 and K562R), and mice bearing tumor as well. The SAR of this chemtypes of Bcr-Abl(T315I) inhibitors will be preliminary elucidated. This project will expand the diversity of Bcr-Abl(T315I) inhibitors, and lay the foundation for the discovery of novel anti-leukemia candidates with high efficiency against resistance induced by T315I mutant.