Development of selective covalent Janus kinase 3 inhibitors

Li Tan, Koshi Akahane, Randall McNally, Kathleen M. S. E. Reyskens, Scott B. Ficarro, Suhu Liu, Grit S. Herter-Sprie, Shohei Koyama, Michael J. Pattison, Katherine Labella, Liv Johannessen, Esra A. Akbay, Kwok Kin Wong, David A. Frank, Jarrod A. Marto, Thomas A. Look, J. Simon C Arthur, Michael J. Eck, Nathanael S. Gray (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)


The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology. (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)6589-6606
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number16
Publication statusPublished - 27 Aug 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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