基于Tubulysins类似物的靶向白血病干细胞抗体偶联物的设计、合成与生物活性研究

The main problems existing in the treatment of leukemia is recurrence and metastasis. Leukemia stem cells are regarded as the origin of recurrence and metastasis. Therefore, selective removal of leukemia stem cells may cure leukemia. However, there is no treatment of selective depletion of LSC. Antibody-chemical drugs conjugates, showing superiorities of the antibodies and chemotherapy drugs, have the advantages of high efficiency and low toxicity. Our preliminary research found the novel tubulysins analogues with the cytotoxicity to pmol level. Its mechanism of action is clear and the action site is unique, but its stability needs to be further improved. On these basis, this project aims to further optimize their structures and total synthesis of series of tubulysins analogues, and evaluate their cytotoxicity and stability to reveal the structure-activity-stability relationships. We expect to find efficient and stable compounds; and then combining it with CD123 antibody which can target LSCs to construct novel of antibody drug conjugates. We evaluate their affinity, the internalization, efficiency, pharmacokinetics, in vitro and in vivo activity in order to find antibody drug conjugates which can target leukemia stem cells and does not damage the normal stem cells. These research might provide a new thought for the cure of leukemia.

白血病治疗存在的主要问题是复发和转移，白血病干细胞（leukemia stem cells, LSCs）可能是白血病复发和转移的根源，选择性清除LSCs可能根治白血病，但目前尚无选择性清除LSCs的治疗方法。抗体-化学药物偶联药物充分发挥了抗体和化疗药物二者的优势，具有高效、低毒等优点。我们前期发现了结构新颖的、细胞毒活性达pmol级tubulysins类似物，作用机制明确、作用位点独特，但其稳定性有待进一步改善。在此基础上，本项目拟进一步优化并全合成系列tubulysins类似物，对其进行活性、稳定性测试，揭示结构-活性-稳定性关系，期望发现高效、稳定的化合物；然后将其与靶向LSCs的抗CD123抗体偶联，构建新型的抗体偶联物，对其进行亲和性、内化效率、药代动力学、体内外活性等评价，以期发现能靶向白血病干细胞、而不损伤正常干细胞的抗体偶联物，为根治白血病提供一个新的思路。

白血病治疗存在的主要问题是复发和转移，白血病干细胞（LSCs）可能是白血病复发和转移的根源，选择性清除LSCs可能根治癌症，但目前的临床药物毒性大不能选择性清除LSCs。抗体偶联药物发挥了抗体和化疗药物二者的优势，具有高效、低毒等优势。发现了结构新颖的pmol级tubulysins类似物，作用机制明确、作用位点独特。进一步设计并全合成系列tubulysins类似物，总结了构效关系，但Tubulysins类似物毒性较大，为了提高其肿瘤靶向性，设计了能靶向肿瘤的偶联物，为发现高效低毒的新型抗肿瘤药物奠定基础。本项目支持下，同时对其他结构类型的天然产物进行了较系统的修饰，总结了构效关系，发现了若干高效低毒的活性化合物，并对活性较高的活性化合物的初步作用机理进行了探讨，为后续进一步发现高活性抗癌化合物提供指导。.发表研究论文16篇，其中第一或通讯作者论文14篇，包括药物化学领域顶级期刊J Med Chem 1篇，J Hemotol Oncol 1篇，Eur J Med Chem 5篇；申请专利5项；指导毕业硕士研究生2名，获得第二十届中国药学会-施维雅青年药物化学奖。.