摘要
骨化性纤维发育不良(FOP # 135100,MIM)是罕见的遗传疾病中的软骨内异位骨化,导致软组织转变成间断性的骨形成。当前,对FOP还没有建立起既定的有效治疗方案 。致病基因突变杂合已经被确认为为细胞内glycine-serine-rich(GS)域或激酶结构域ALK2(Activin-like kinase-2,也称为激活素受体I型,ACVR1)、I型受体的骨形成蛋白(BMP)。不断的研究表明,这些突变异常激活BMP信号配体蛋白依赖的方式通过减少与负监管机构FKBP12 ALK2的互动。而其他人认为FOP 配体蛋白依赖 BMP信号激活。然而,在非配体蛋白依赖t或配体蛋白依赖t模型中,ALK2受体激活的异位骨化FOP至关重要。因此以ALK2为靶点可能代表一个针对FOP有效的治疗方案。在本文中,我们仔细审阅最近进展的治疗策略,重点发展小分子ALK2抑制剂抑针对FOP治疗来抑制BMP信号。
关键词: FOP,ALK2,BMP,激酶,小分子,抑制剂,核视黄酸受体γ,异位骨化
Current Molecular Medicine
Title:Development of New Therapeutic Agents for Fibrodysplasia Ossificans Progressiva.
Volume: 16 Issue: 1
Author(s): Y. Luo, A. Alsamarah, K. Zhang and J. Hao
Affiliation:
关键词: FOP,ALK2,BMP,激酶,小分子,抑制剂,核视黄酸受体γ,异位骨化
摘要: Fibrodysplasia ossificans progressiva (FOP, MIM #135100) is a rare genetic disorder of heterotopic endochondral ossification, resulting in transformation of soft tissue into episodic bone formation. Currently, no effective treatment for FOP has been established. The causative heterozygous genetic mutations have been identified in either the intracellular glycine-serine-rich (GS) domain or kinase domain of ALK2 (Activin-like kinase-2, also known as Activin A receptor type I, ACVR1), a type I receptor of bone morphogenetic proteins (BMP). Cumulative studies support that these mutations abnormally activate BMP signaling in a ligandindependent manner by reducing the ALK2 interaction with the negative regulator FKBP12, whereas others argue a ligand-dependent BMP signaling activation in FOP. Nevertheless, in either the ligand-independent or ligand-dependent model, ALK2 receptor activation is essential for heterotopic ossification in FOP. Thus targeting ALK2 likely represents an effective treatment for FOP. In this article, we critically review the recent progress on therapeutic strategies, with a focus on development of small molecule ALK2 inhibitors to suppress BMP signaling for FOP treatment.
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Cite this article as:
Y. Luo, A. Alsamarah, K. Zhang and J. Hao , Development of New Therapeutic Agents for Fibrodysplasia Ossificans Progressiva., Current Molecular Medicine 2016; 16 (1) . https://dx.doi.org/10.2174/1566524016666151222142446
DOI https://dx.doi.org/10.2174/1566524016666151222142446 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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