ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma

被引:0
|
作者
Sekimata, Katsuhiko [1 ]
Sato, Tomohiro [2 ]
Sakai, Naoki [3 ]
机构
[1] RIKEN, Ctr Sustainable Resource Sci, Drug Discovery Chem Platform Unit, 2-1 Hirosawa, Wako, Saitama 3510198, Japan
[2] RIKEN, Ctr Biosyst Dynam Res, Drug Discovery Computat Chem Platform Unit, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan
[3] RIKEN, Biosyst Dynam Res, Drug Discovery Struct Biol Platform Unit, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan
关键词
activin receptor-like kinase-2 (ALK2); drug discovery; rare disease; fibrodysplasia ossificans progressive (FOP); diffuse intrinsic pontine glioma (DIPG); ACVR1; MUTATIONS; HETEROTOPIC OSSIFICATION; SOMATIC MUTATIONS; GENOMIC LANDSCAPE; RECEPTOR; BETA; INHIBITION; GROWTH; SUBGROUPS; CHILDREN;
D O I
暂无
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.
引用
收藏
页码:194 / 200
页数:7
相关论文
共 50 条
  • [1] Molecular dynamics study of ALK2 kinase mutations in fibrodysplasia ossificans progressiva disorder
    Luo, Yun
    Alsamarah, Abdelaziz
    Hao, Jijun
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 251
  • [2] Structure of the Bone Morphogenetic Protein Receptor ALK2 and Implications for Fibrodysplasia Ossificans Progressiva
    Chaikuad, Apirat
    Alfano, Ivan
    Kerr, Georgina
    Sanvitale, Caroline E.
    Boergermann, Jan H.
    Triffitt, James T.
    von Delft, Frank
    Knapp, Stefan
    Knaus, Petra
    Bullock, Alex N.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (44) : 36990 - 36998
  • [3] Revealing Activation Mechanism of Alk2 Kinase Mutations in Fibrodysplasia Ossificans Progressiva (FOP)
    Alsamarah, Abdelaziz
    Hao, Jijun
    Luo, Yun
    [J]. BIOPHYSICAL JOURNAL, 2016, 110 (03) : 206A - 206A
  • [4] BLU-782; a highly selective ALK2 inhibitor, designed specifically to target the cause of fibrodysplasia ossificans progressiva
    Davis, Alison
    Hodous, Brian
    Labranche, Timothy
    Sheets, Michael
    Brooijmans, Natasja
    Kim, Joseph
    Williams, Brett
    Kim, Sean
    Xu, Lan
    Vassiliadis, John
    Zhu, Julia
    Wang, Ruduan
    Stewart, Rachel
    Fleming, Paul
    Graul, Chris
    Greenblatt, Elliot
    Bouchard, Keith
    Kadambi, Vivek
    Guzi, Timothy
    Hunter, Jeffrey
    Lengauer, Christoph
    Dorsch, Marion
    Garner, Andrew
    [J]. JOURNAL OF BONE AND MINERAL RESEARCH, 2018, 33 : 26 - 26
  • [5] Alk2 Regulates Early Chondrogenic Fate in Fibrodysplasia Ossificans Progressiva Heterotopic Endochondral Ossification
    Culbert, Andria L.
    Chakkalakal, Salin A.
    Theosmy, Edwin G.
    Brennan, Tracy A.
    Kaplan, Frederick S.
    Shore, Eileen M.
    [J]. STEM CELLS, 2014, 32 (05) : 1289 - 1300
  • [6] Rational design of ALK2 small molecule inhibitors for treatment of fibrodysplasia ossificans progressiva (FOP)
    Luo, Yun
    Alsamarah, Abdelaziz
    [J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2015, 249
  • [7] RECURRENT ACTIVATING ACVR1/ALK2 MUTATIONS IN DIFFUSE INTRINSIC PONTINE GLIOMA
    Taylor, Katy
    Mackay, Alan
    Truffaux, Nathalene
    Morozova, Olena
    Butterfield, Yaron
    Phillipe, Cathy
    Vinci, Maria
    de Torres, Carmen
    Cruz, Ofelia
    Mora, Jaume
    Hargrave, Darren
    Monje, Michelle
    Puget, Stephanie
    Yip, Stephen
    Jones, Chris
    Grill, Jacques
    [J]. NEURO-ONCOLOGY, 2013, 15 : 174 - 175
  • [8] How Activin A Became a Therapeutic Target in Fibrodysplasia Ossificans Progressiva
    Srinivasan, Dushyanth
    Arostegui, Martin
    Goebel, Erich J.
    Hart, Kaitlin N.
    Aykul, Senem
    Lees-Shepard, John B.
    Idone, Vincent
    Hatsell, Sarah J.
    Economides, Aris N.
    [J]. BIOMOLECULES, 2024, 14 (01)
  • [9] Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma
    Ensan, Deeba
    Smil, David
    Zepeda-Velazquez, Carlos A.
    Panagopoulos, Dimitrios
    Wong, Jong Fu
    Williams, Eleanor P.
    Adamson, Roslin
    Bullock, Alex N.
    Kiyota, Taira
    Aman, Ahmed
    Roberts, Owen G.
    Edwards, Aled M.
    O'Meara, Jeff A.
    Isaac, Methvin B.
    Al-awar, Rima
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (09) : 4978 - 4996
  • [10] Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva
    Sun, Liping
    Jin, Yonghui
    Nishio, Megumi
    Watanabe, Makoto
    Kamakura, Takeshi
    Nagata, Sanae
    Fukuda, Masayuki
    Maekawa, Hirotsugu
    Kawai, Shunsuke
    Yamamoto, Takuya
    Toguchida, Junya
    [J]. LIFE SCIENCE ALLIANCE, 2024, 7 (05)