An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva.
An mTOR Signaling Modulator Suppressed Heterotopic Ossification of Fibrodysplasia Ossificans Progressiva.
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DOI：
10.1016/j.stemcr.2018.10.007
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发表时间：
2018-11-13
影响因子：
5.9
通讯作者：
Ikeya M
中科院分区：
文献类型：
--
作者：
Hino K;Zhao C;Horigome K;Nishio M;Okanishi Y;Nagata S;Komura S;Yamada Y;Toguchida J;Ohta A;Ikeya M
进行性骨化性纤维发育不良（FOP）是一种罕见的难治性疾病，其特征是通过软骨内骨化形成骨外骨。FOP患者在ACVR 1（FOP-ACVR 1）中存在功能获得性突变，ACVR 1是骨形态发生蛋白的I型受体。尽管有许多研究，但没有药物被批准用于FOP。在这里，我们开发了一种高通量筛选（HTS）系统，重点是通过利用稳定表达FOP-ACVR 1的软骨形成ATDC 5细胞系组成型激活FOP-ACVR 1。在对5，000种小分子化合物进行HTS后，我们鉴定出两种有效抑制FOP患者来源的诱导多能干细胞（FOP-iPSC）的增强软骨形成并抑制多个模型小鼠（包括FOP-ACVR 1转基因小鼠和利用FOP-iPSC的HO模型小鼠）的异位骨化（HO）的命中化合物。此外，我们发现其中一种命中化合物是间接抑制mTOR信号传导的mTOR信号传导调节剂。我们的研究结果表明，这些命中化合物可能有助于未来的药物重新定位和mTOR信号传导的机制分析。建立了进行性骨化性纤维发育不良（FOP）的筛选系统确定了两种在多种FOP模型小鼠中有效的命中化合物一种mTOR信号转导调节剂为治疗策略打开了大门关注进行性骨化性纤维发育不良（FOP）患者中突变ACVR 1的配体非依赖性组成性激活，Ikeya及其同事已经确定了两种在多种FOP模型小鼠中有效的命中化合物。其中一种热门化合物TAK 165是一种mTOR信号调节剂，间接调节增强的mTOR信号。这些发现揭示了FOP的治疗策略。
Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disorder characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor gain-of-function mutations in ACVR1 (FOP-ACVR1), a type I receptor for bone morphogenetic proteins. Despite numerous studies, no drugs have been approved for FOP. Here, we developed a high-throughput screening (HTS) system focused on the constitutive activation of FOP-ACVR1 by utilizing a chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS of 5,000 small-molecule compounds, we identified two hit compounds that are effective at suppressing the enhanced chondrogenesis of FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and suppressed the heterotopic ossification (HO) of multiple model mice, including FOP-ACVR1 transgenic mice and HO model mice utilizing FOP-iPSCs. Furthermore, we revealed that one of the hit compounds is an mTOR signaling modulator that indirectly inhibits mTOR signaling. Our results demonstrate that these hit compounds could contribute to future drug repositioning and the mechanistic analysis of mTOR signaling. Established a screening system for fibrodysplasia ossificans progressiva (FOP) Identified two hit compounds that are effective in multiple FOP model mice An mTOR signaling modulator opens the door to a therapeutic strategy Focusing on the ligand-independent constitutive activation of mutated ACVR1 in fibrodysplasia ossificans progressiva (FOP) patients, Ikeya and colleagues have identified two hit compounds that were effective in multiple FOP model mice. One of the hit compounds, TAK 165, was an mTOR signaling modulator that indirectly regulated enhanced mTOR signaling. These findings shed light on a therapeutic strategy for FOP.
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影响因子：
3.7
作者：
Fukuta M;Nakai Y;Kirino K;Nakagawa M;Sekiguchi K;Nagata S;Matsumoto Y;Yamamoto T;Umeda K;Heike T;Okumura N;Koizumi N;Sato T;Nakahata T;Saito M;Otsuka T;Kinoshita S;Ueno M;Ikeya M;Toguchida J
通讯作者：
Toguchida J
影响因子：
4.3
作者：
Cappato S;Tonachini L;Giacopelli F;Tirone M;Galietta LJ;Sormani M;Giovenzana A;Spinelli AE;Canciani B;Brunelli S;Ravazzolo R;Bocciardi R
通讯作者：
Bocciardi R
新型和选择性骨形态发生蛋白受体（BMP）抑制剂的合成和结构活性关系从吡唑洛斯[1.5-A]吡胺胺的嘧啶支架衍生而来：ML347的发现ML347作为ALK2对ALK2对ALK3对ALK3的选择性MLPCN探针。
影响因子：
2.7
作者：
Engers, Darren W.;Frist, Audrey Y.;Lindsley, Craig W.;Hong, Charles C.;Hopkins, Corey R.
通讯作者：
Hopkins, Corey R.
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1002/jbmr.2820
发表时间：
2016-09
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Chakkalakal SA;Uchibe K;Convente MR;Zhang D;Economides AN;Kaplan FS;Pacifici M;Iwamoto M;Shore EM
通讯作者：
Shore EM