2. Academic Validation
  3. Tubulosine selectively inhibits JAK3 signalling by binding to the ATP-binding site of the kinase of JAK3

Tubulosine selectively inhibits JAK3 signalling by binding to the ATP-binding site of the kinase of JAK3

  • J Cell Mol Med. 2020 Jul;24(13):7427-7438. doi: 10.1111/jcmm.15362.
Byung-Hak Kim 1 2 3,  Eun Hee Yi 2 4,  Jun-Goo Jee 5,  Ae Jin Jeong 2 3,  Claudio Sandoval 1,  In-Chul Park 6,  Gyeong Hun Baeg 1 7,  Sang-Kyu Ye 2 3 4 8
Affiliations

Affiliations

  • 1 Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
  • 2 Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 3 Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 4 Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 5 Research Institute of Pharmaceutical Researches, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
  • 6 Division of Basic Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
  • 7 School of Life and Health Sciences, Chinese University of Hong Kong, Shenzhen, China.
  • 8 Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
PMID: 32558259 DOI: 10.1111/jcmm.15362
Abstract

Gain- or loss-of-function mutations in Janus kinase 3 (JAK3) contribute to the pathogenesis of various haematopoietic malignancies and immune disorders, suggesting that aberrant JAK3 signalling is an attractive therapeutic target to treat these disorders. In this study, we performed structure-based computational database screening using the 3D structure of the JAK3 kinase domain and the National Cancer Institute diversity set and identified tubulosine as a novel JAK3 Inhibitor. Tubulosine directly blocked the catalytic activity of JAK3 by selective interacting with the JAK3 kinase domain. Consistently, tubulosine potently inhibited persistently activated and interleukin-2-dependent JAK3, and JAK3-mediated downstream targets. Importantly, it did not affect the activity of Other JAK family members, particularly prolactin-induced JAK2/signal transducer and activator of transcription 5 and interferon alpha-induced JAK1-TYK2/STAT1. Tubulosine specifically decreased survival and proliferation of Cancer cells, in which persistently active JAK3 is expressed, by inducing apoptotic and necrotic/autophagic cell death without affecting Other oncogenic signalling. Collectively, tubulosine is a potential small-molecule compound that selectively inhibits JAK3 activity, suggesting that it may serve as a promising therapeutic candidate for treating disorders caused by aberrant activation of JAK3 signalling.

Keywords

JAK3; STAT; leukaemia; lymphoma; structure-based computational database screening; tubulosine.

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