Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome.
Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome.
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基于多能干细胞的筛选将CUDC-907鉴定为恢复Nakajo-Nishimura综合征体外表型的有效化合物。
DOI：
10.1002/sctm.20-0198
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发表时间：
2021-03
影响因子：
6
通讯作者：
Saito MK
中科院分区：
文献类型：
--
作者：
Kase N;Terashima M;Ohta A;Niwa A;Honda-Ozaki F;Kawasaki Y;Nakahata T;Kanazawa N;Saito MK
Nakajo-Nishimura综合征(NNS)是一种由PSMB8基因纯合突变引起的自身炎症性疾病。全身应用皮质类固醇部分有效，但持续治疗会产生严重的副作用。我们以前建立了一种多能干细胞(PSC)来源的NNS疾病模型，该模型复制了几种炎症表型，包括单核细胞趋化蛋白-1(MCP-1)和干扰素-γ诱导蛋白-10(IP-10)的过度产生。在这里，我们使用PSC衍生的NNS模型进行高通量化合物筛选(HTS)以寻找潜在的治疗候选者，并确定CUDC-907是MCP-1和IP-10释放的有效抑制剂。CUDC-907的短期治疗在治疗浓度范围内不会诱导细胞死亡，对原发患者细胞也有效。进一步的分析表明，这种抑制作用是转录后的。这些发现表明，HTS与PSC衍生的疾病模型在寻找治疗自身炎症性疾病的候选药物方面是有用的。使用多能干细胞来源的单核细胞系进行高通量筛选，以确定Nakajo-Nishimura综合征的潜在治疗候选者。HIT化合物CUDC-907有效地抑制炎性趋化因子、单核细胞趋化蛋白-1和干扰素诱导的蛋白-10的过度产生。
Nakajo‐Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)‐derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein‐1 (MCP‐1) and interferon gamma‐induced protein‐10 (IP‐10). Here we performed high‐throughput compound screening (HTS) using this PSC‐derived NNS model to find potential therapeutic candidates and identified CUDC‐907 as an effective inhibitor of the release of MCP‐1 and IP‐10. Short‐term treatment of CUDC‐907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post‐transcriptional. These findings suggest that HTS with PSC‐derived disease models is useful for finding drug candidates for autoinflammatory diseases. High‐throughput screening using pluripotent stem cell‐derived monocytic cell lines was performed to identify potential therapeutic candidates of Nakajo‐Nishimura syndrome. The hit compound, CUDC‐907 effectively inhibits the overproduction of inflammatory chemokines, monocyte chemoattractant protein‐1, and interferon gamma‐induced protein‐10.
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影响因子：
11.4
作者：
Deleu, S.;Lemaire, M.;Vanderkerken, K.
通讯作者：
Vanderkerken, K.
影响因子：
11.5
作者：
Qian, Changgeng;Lai, Cheng-Jung;Voi, Maurizio
通讯作者：
Voi, Maurizio
影响因子：
3.8
作者：
Drutskaya, Marina S.;Efimov, Grigory A.;Nedospasov, Sergei A.
通讯作者：
Nedospasov, Sergei A.
DOI：
10.1038/nrm3741
发表时间：
2014-02
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
Eckschlager T;Plch J;Stiborova M;Hrabeta J
通讯作者：
Hrabeta J