2. Academic Validation
  3. Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine

Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine

  • Nat Chem Biol. 2022 Sep 12. doi: 10.1038/s41589-022-01098-0.
Madeline E Kavanagh  # 1,  Benjamin D Horning  # 2,  Roli Khattri 2,  Nilotpal Roy 2,  Justine P Lu 2,  Landon R Whitby 2,  Elva Ye 1,  Jaclyn C Brannon 2,  Albert Parker 2,  Joel M Chick 2,  Christie L Eissler 2,  Ashley J Wong 2,  Joe L Rodriguez 2,  Socorro Rodiles 2,  Kim Masuda 1,  John R Teijaro 3,  Gabriel M Simon 2,  Matthew P Patricelli 4,  Benjamin F Cravatt 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Scripps Research, La Jolla, CA, USA.
  • 2 Vividion Therapeutics, San Diego, CA, USA.
  • 3 Department of Immunology and Microbial Science, Scripps Research, La Jolla, CA, USA.
  • 4 Vividion Therapeutics, San Diego, CA, USA. [email protected].
  • 5 Department of Chemistry, Scripps Research, La Jolla, CA, USA. [email protected].
  • # Contributed equally.
PMID: 36097295 DOI: 10.1038/s41589-022-01098-0
Abstract

The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and Tyk2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and Tyk2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as 'silent' ligands for Tyk2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.

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