最近出版的《自然—化學(xué)生物學(xué)》報(bào)道了一種小分子可通過結(jié)合并激活死亡受體5（DR5）實(shí)現(xiàn)誘導(dǎo)產(chǎn)生選擇性癌細(xì)胞凋亡,。
腫瘤壞死因子（TNF）及相關(guān)分子諸如TRAIL屬于信號(hào)蛋白，可在細(xì)胞表面與死亡受體結(jié)合并激活細(xì)胞凋亡通路,。這種細(xì)胞促凋亡通路的數(shù)個(gè)明顯階段已被用于誘導(dǎo)癌細(xì)胞選擇性凋亡,，以研究出更多有效的癌癥治療方法。比如,，模擬Smac分子的化合物可以激活相關(guān)通路的下游部分,。同樣地，一類以死亡受體為標(biāo)靶的治療方法也曾獲得研究,，包括利用TNF本身或者針對(duì)相關(guān)細(xì)胞表面受體的抗體,，但這類治療方法的開發(fā)因意外產(chǎn)生的毒副作用而受阻。
Xiaodong Wang等人報(bào)告了一種化學(xué)篩選方法,，利用該方法篩選出的一類小分子可與Smac類似物協(xié)同激活DR5,。利用這種篩選方法，研究人員發(fā)現(xiàn)了名為bioymifi的DR5活化劑，該活化劑可作為單獨(dú)試劑或者與Smac類似物相結(jié)合,，誘導(dǎo)產(chǎn)生選擇性癌細(xì)胞凋亡,。他們認(rèn)為，bioymifi代表了一種直接激活癌細(xì)胞中DR5的新策略并有望幫助開發(fā)新的抗癌療法,。(生物谷Bioon.com)
doi:10.1038/nchembio.1153
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PMID:
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.
