最近出版的《自然—化学生物学》报道了一种小分子可通过结合并激活死亡受体5（DR5）实现诱导产生选择性癌细胞凋亡。
肿瘤坏死因子（TNF）及相关分子诸如TRAIL属于信号蛋白，可在细胞表面与死亡受体结合并激活细胞凋亡通路。这种细胞促凋亡通路的数个明显阶段已被用于诱导癌细胞选择性凋亡，以研究出更多有效的癌症治疗方法。比如，模拟Smac分子的化合物可以激活相关通路的下游部分。同样地，一类以死亡受体为标靶的治疗方法也曾获得研究，包括利用TNF本身或者针对相关细胞表面受体的抗体，但这类治疗方法的开发因意外产生的毒副作用而受阻。
Xiaodong Wang等人报告了一种化学筛选方法，利用该方法筛选出的一类小分子可与Smac类似物协同激活DR5。利用这种筛选方法，研究人员发现了名为bioymifi的DR5活化剂，该活化剂可作为单独试剂或者与Smac类似物相结合，诱导产生选择性癌细胞凋亡。他们认为，bioymifi代表了一种直接激活癌细胞中DR5的新策略并有望帮助开发新的抗癌疗法。(生物谷Bioon.com)
doi:10.1038/nchembio.1153
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Small-molecule activation of the TRAIL receptorDR5 in human cancer cells
Gelin Wang, Xiaoming Wang, Hong Yu, Shuguang Wei, Noelle Williams, Daniel L Holmes,Randal Halfmann, Jacinth Naidoo, Lai Wang, Lin Li, She Chen, Patrick Harran, Xiaoguang Lei& Xiaodong Wang
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates apoptosis through the death receptors DR4 and DR5. Because of its superior safety profile and high tumor specificity compared to other TNF family members, recombinant soluble TRAIL and agonistic antibodies against its receptors are actively being developed for clinical cancer therapy. Here, we describe the identification and characterization of the small molecules that directly target DR5 to initiate apoptosis in human cancer cells. The activity was initially discovered through a high-throughput chemical screen for compounds that promote cell death in synergy with a small-molecule mimetic ofSmac, the antagonist for inhibitor of apoptosis protein. Structure-activity relationship studies yielded a more potent analog called bioymifi, which can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis. Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy.
