Generation of a chemical genetic model for JAK3

Judit Remenyi, Rangeetha J. Naik, Jinhua Wang, Momchil Razsolkov, Alyssa Verano, Quan Cai, Li Tan, Rachel Toth, Samantha Raggett, Carla Baillie, Ryan Traynor, James Hastie, Nathanael S. Gray, Simon C. Arthur (Lead / Corresponding author)

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Abstract

Janus Kinases (JAKs) have emerged as an important drug target for the treatment of a number of immune disorders due to the central role that they play in cytokine signalling. 4 isoforms of JAKs exist in mammalian cells and the ideal isoform profile of a JAK inhibitor has been the subject of much debate. JAK3 has been proposed as an ideal target due to its expression being largely restricted to the immune system and its requirement for signalling by cytokine receptors using the common γ-chain. Unlike other JAKs, JAK3possesses a cysteine in its ATP binding pocket and this has allowed the design of isoform selective covalentJAK3 inhibitors targeting this residue. We report here that mutating this cysteine to serine does not preventJAK3 catalytic activity but does greatly increase the IC50 for covalent JAK3 inhibitors. Mice with aCys905Ser knock in mutation in the endogenous JAK3 gene are viable and show no apparent welfare issues. Cells from these mice show normal STAT phosphorylation in response to JAK3 dependent cytokines but are resistant to the effects of covalent JAK3 inhibitors. These mice therefore provide a chemical-genetic model to study JAK3 function.
Original languageEnglish
Article number10093
Number of pages13
JournalScientific Reports
Volume11
Issue number1
Early online date12 May 2021
DOIs
Publication statusE-pub ahead of print - 12 May 2021

Keywords

  • Cytokines
  • Immunology
  • Kinases
  • Medicinal chemistry

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