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

Byung‐Hak Kim,In‐Chul Park,Ae Jin Jeong,Sang‐Kyu Ye,Jun‐Goo Jee,Claudio Sandoval,Eun Hee Yi,Gyeong Hun Baeg

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.

Highlights

Cytokines are critical signalling molecules that regulate various biological responses, including cell proliferation, differentiation, tissue homeostasis, haematopoiesis and immune responses
The mammalian Janus family of protein tyrosine kinases (JAKs) family consists of four members: JAK1, JAK2, Janus kinase 3 (JAK3) and TYK2, and the STAT substrate family consists of seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.2 In particular, JAK3 is predominantly expressed in haematopoietic cell lineages such as lymphoid cells and mediates receptor-mediated cytokine signalling involving interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21.3 These cytokines transduce JAK3/STAT signalling cascades through the common gamma chain subfamily of cytokine receptors paired with an alpha or beta chain as signalling partners.[2,3]
We identified tubulosine as a potent and selective JAK3 inhibitor that predominantly targeted the enzyme activity of JAK3 kinase, as compared to other JAK family members

Summary

Introduction

Cytokines are critical signalling molecules that regulate various biological responses, including cell proliferation, differentiation, tissue homeostasis, haematopoiesis and immune responses. The mammalian JAK family consists of four members: JAK1, JAK2, Janus kinase 3 (JAK3) and TYK2, and the STAT substrate family consists of seven members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6.2 In particular, JAK3 is predominantly expressed in haematopoietic cell lineages such as lymphoid cells and mediates receptor-mediated cytokine signalling involving interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21.3 These cytokines transduce JAK3/STAT signalling cascades through the common gamma chain (γc) subfamily of cytokine receptors paired with an alpha or beta chain as signalling partners.[2,3] They thought to be involved in T-cell development and immune homeostasis, as loss-of-function JAK3 mutations in humans have been shown to result in haematopoietic disorders such as severe combined immunodeficiency (SCID).[4,5] Further, gene therapy for autosomal recessive SCID using haematopoietic stem cell transplantation increased the risk of acute T-cell leukaemia due to the direct activation of the γc-mediated JAK3/signal transducer and activator of transcription 5 (STAT5) signalling.[6]

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