靶向TRIP13小分子化合物TI17抵抗骨髓瘤耐药的效应及机制研究

Multiple myeloma (MM) is an incurable hematological malignancy, of which drug resistance plays a critical role in MM recurrence and progression.TRIP13 (Thyroid hormone receptor interactor 13) matters much in the cell mitosis, as well as recombination and structure of chromosomes. In the previous study, we found that overexpression of TRIP13 was closely related to MM recurrence, drug resistance and poor prognosis, suggesting that TRIP13 might represent an important therapeutic target for MM. However, up to now, there is no small molecule compound targeting TRIP13 internationally. Here, to identify small molecule inhibitors of TRIP13，we performed computer virtual screening and activity detection in vitro. As a result, we identified active small compound TI17 that specifically targeted TRIP13 in vitro and suppressed Velcade resistant MM cells. Moreover, the application of national invention patent of TI17 has been approved. By using structural biology, molecular simulation, molecular biology, functional genomics and proteomics and other technologies, we will investigate the function and activity regulation of TI17 and further analyze its pharmacokinetics in vivo. Finally, we will clarify the effect and relevant mechanism of TI17 and its drug combination in killing drug resistance MM cells, as well as acquire independent intellectual property rights of anti-MM small molecule drugs. Our investigation provides new insights into therapeutic strategies for relapsed / refractory MM and achieves well prospects for clinical application.

多发性骨髓瘤（MM）是不可治愈的血液系统恶性肿瘤，MM细胞耐药在MM复发和进展过程中起关键作用。TRIP13（甲状腺激素受体相互作用13）在细胞有丝分裂阶段，对染色体的重组和结构完善具有重要作用。我们前期研究发现，TRIP13高表达与MM复发、耐药及不良预后密切相关,推测TRIP13可作为潜在的治疗靶标，但至今尚无靶向TRIP13的化合物。我们通过计算机虚拟筛选和体外活性检测，发现一种活性小分子化合物TI17与TRIP13在体外有特异性结合，且能有效抑制万珂耐药MM细胞生长，并已获国家发明专利申请号。本项目拟应用结构生物学、分子模拟、分子生物学、功能基因组学和蛋白质组学等技术，探索TI17的功能和活性调控；阐明TI17单独或联合用药杀伤耐药MM细胞的效应及作用机制；分析其在动物体内的药代动力学，将有望获得有自主知识产权的抗MM小分子药物,为复发/难治MM治疗提供新思路，具有临床应用前景。

甲状腺激素受体相互作用蛋白13（TRIP13）高表达与多发性骨髓瘤（MM）复发、耐药及不良预后密切相关，推测TRIP13可作为MM潜在的治疗靶标，但至今尚无靶向TRIP13的化合物。我们通过计算机虚拟筛选和体外活性检测，发现小分子化合物TI17与TRIP13在体外有特异性结合。我们阐明了靶向TRIP13化合物TI17与TRIP13相互作用的模式，为我们课题组进一步优化TI17结构，以获得新型优效的化合物提供了实验依据。阐明了TI17抑制MM细胞增殖和诱导凋亡的作用，TI17通过上调γ-H2AX的蛋白表达，使ATM及其阐明下游Chk2发生磷酸化而发挥作用。我们研究也明确了TI17与临床MM药物马法兰或组蛋白去乙酰化酶（HDAC）抑制剂联合杀伤MM细胞的效应及分子机制，本研究为MM治疗提供了新思路，具有潜在的临床应用前景。同时，为了更深入探讨MM发病机制，研究干预MM的新策略，在本基金的资助下，开展了具有潜在转化前景的具有我们课题组自主知识产权的新型小分子化合物抗MM作用及机制的探索性研究，取得了可喜的成果。.已经发表标注本基金号的SCI论著5篇，影响因子（IF）大于7分的2篇，IF共23.5分，其中第一标注本基金号的SCI论著4篇，IF共16.5分，IF大于7分的1篇。已发表第二标注本基金号的SCI论著1篇，IF 7.068分。申请国家发明专利1项，并已经获得国家发明专利授权。培养博士研究生2名。参加国内和国际学术会议共7人次。