Small molecules inhibitors of the heterogeneous ribonuclear protein A18 (hnRNP A18): a regulator of protein translation and an immune checkpoint.
Small molecules inhibitors of the heterogeneous ribonuclear protein A18 (hnRNP A18): a regulator of protein translation and an immune checkpoint.
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DOI：
10.1093/nar/gkaa1254
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发表时间：
2021-02-22
影响因子：
14.9
通讯作者：
Carrier F
中科院分区：
文献类型：
--
作者：
Solano-Gonzalez E;Coburn KM;Yu W;Wilson GM;Nurmemmedov E;Kesari S;Chang ET;MacKerell AD;Weber DJ;Carrier F
我们已经确定了同时抑制癌细胞进展和免疫检查点的化学探针。使用配体竞争饱和（SILCS）技术，结构生物学和基于细胞的测定的计算位点识别，我们确定了直接和选择性地结合到hnRNP A18的RNA识别基序（RRM）的小分子，hnRNP A18是癌细胞中蛋白质翻译的调节剂。hnRNP A18识别与癌细胞进展相关的转录物（Trx、VEGF、RPA）的3′UTR中的特异性RNA特征基序，以及肿瘤免疫检查点（CTLA-4）。免疫检查点的转录后调控是一种潜在的治疗策略，仍有待开发。探针在体外和细胞中靶向hnRNP A18 RRM，如通过细胞靶向接合所评估的。作为单一试剂，探针特异性地破坏hnRNP A18-RNA相互作用，下调Trx和CTLA-4蛋白水平，并抑制几种癌细胞系的增殖，而不影响正常上皮细胞的活力。这些一流的化学探针将极大地促进阐明癌细胞中RNA结合蛋白（RBP）的未充分探索的生物学功能，包括它们对增殖和免疫检查点激活的影响。
We have identified chemical probes that simultaneously inhibit cancer cell progression and an immune checkpoint. Using the computational Site Identification by Ligand Competitive Saturation (SILCS) technology, structural biology and cell-based assays, we identify small molecules that directly and selectively bind to the RNA Recognition Motif (RRM) of hnRNP A18, a regulator of protein translation in cancer cells. hnRNP A18 recognizes a specific RNA signature motif in the 3′UTR of transcripts associated with cancer cell progression (Trx, VEGF, RPA) and, as shown here, a tumor immune checkpoint (CTLA-4). Post-transcriptional regulation of immune checkpoints is a potential therapeutic strategy that remains to be exploited. The probes target hnRNP A18 RRM in vitro and in cells as evaluated by cellular target engagement. As single agents, the probes specifically disrupt hnRNP A18–RNA interactions, downregulate Trx and CTLA-4 protein levels and inhibit proliferation of several cancer cell lines without affecting the viability of normal epithelial cells. These first-in-class chemical probes will greatly facilitate the elucidation of the underexplored biological function of RNA Binding Proteins (RBPs) in cancer cells, including their effects on proliferation and immune checkpoint activation.
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通过配体竞争饱和（SILCS）方法在现场识别中包含多种片段类型。
影响因子：
5.6
作者：
Raman EP;Yu W;Lakkaraju SK;MacKerell AD Jr
通讯作者：
MacKerell AD Jr
富含甘氨酸的RNA结合蛋白，介导了对哺乳动物细胞生长的冷诱导抑制。
影响因子：
7.8
作者：
Nishiyama, H;Itoh, K;Kaneko, Y;Kishishita, M;Yoshida, O;Fujita, J
通讯作者：
Fujita, J
影响因子：
5.6
作者：
Koes DR;Camacho CJ
通讯作者：
Camacho CJ
影响因子：
16.6
作者：
Lopez de Silanes, Isabel;Stagno d'Alcontres, Martina;Blasco, Maria A.
通讯作者：
Blasco, Maria A.
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.