Targeting of DEPTOR in Multiple Myeloma

初步研究表明，mTOR结合蛋白DEPTOR是一个潜在的治疗靶点， 多发性骨髓瘤它在这种疾病中特异性上调，其沉默对骨髓瘤细胞是致命的。我们， 因此，在高通量药物筛选中鉴定了潜在的DEPTOR抑制剂。该抑制剂在以下方面有效： 骨髓瘤细胞具有预期的分子改变和诱导死亡。在本提案中，我们计划 进一步开发这种抑制剂。我们将生产生化衍生物，目的是提高 DEPTOR抑制剂的治疗指数，确定抑制剂首次结合的作用机制， 骨髓瘤细胞，确定对DEPTOR表达缺失的小鼠中正常组织的可能毒性， 评估与临床上使用的其他抗骨髓瘤治疗药物可能的相互作用。我们还将测试 DEPTOR对通过磷酸戊糖分流的流量的影响。我们的期望是这些新药 将是骨髓瘤患者使用的医疗设备的重要补充，此外，它们将 专门针对具有高DEPTOR表达的肿瘤患者。

Preliminary work indicates the mTOR-binding protein DEPTOR is a potential molecular target for therapy in multiple myeloma. It is specifically upregulated in this disease and its silencing is lethal to myeloma cells. We, thus, identified a potential DEPTOR inhibitor in a high-throughput drug screen. The inhibitor is effective in myeloma cells with the expected molecular alterations and induction of death. In this proposal we plan to further develop this inhibitor. We will generate biochemical derivatives with the aim of enhancing the therapeutic index of DEPTOR inhibitors, identify the mechanism of action of where the inhibitors first bind in myeloma cells, ascertain possible toxicity to normal tissues in mice with deleted DEPTOR expression and assess possible interactions with other anti-myeloma therapeutics that are used in the clinic. We will also test the effect of DEPTOR on flux through the pentose phosphate shunt. Our expectation is that these new drugs will be important additions to the armamentarium used in myeloma patients and, furthermore, they will be specifically tailored to patients with tumors that have high DEPTOR expression.