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Molecular Diversity

, Volume 22, Issue 2, pp 343–358 | Cite as

Design, synthesis, and SAR study of highly potent, selective, irreversible covalent JAK3 inhibitors

  • Linhong He
  • Mingfeng Shao
  • Taijin Wang
  • Tingxuan Lan
  • Chufeng Zhang
  • Lijuan Chen
Original Article
  • 283 Downloads

Abstract

Here, we report the design and synthesis of pyrimidinyl heterocyclic compounds containing terminal electrophiles as irreversible covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of the structure–activity relationship utilizing kinase assays resulted in the identification of potent and selective JAK3 inhibitors such as T1, T8, T15, T22, and T29. Among them, T29 was verified as a promising JAK3 irreversible inhibitor that possessed the best bioactivity and selectivity against JAKs and kinases containing a cysteine in the residue analogous to Cys909 in JAK3, suggesting that covalent modification of this Cys residue allowed the identification of a highly selective JAK3 inhibitor. Moreover, T29 also displayed a significant anti-inflammatory effect in ICR mice through the inhibition of increased paw thickness, which is worth further optimization to increase its potency and medicinal properties.

Keywords

JAK3 Covalent inhibitor Selectivity Structure–activity relationship (SAR) Docking 

Abbreviations

JAK

Janus kinase

STAT

Signal transducer and activator of transcription

Cys

Cysteine

SAR

Structure–activity relationship

Notes

Acknowledgements

The authors greatly appreciate the financial support from the National Natural Science Foundation of China (81373260).

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.

Supplementary material

11030_2017_9803_MOESM1_ESM.docx (2.3 mb)
Enzyme potencies and NMR spectrums for all compounds

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Linhong He
    • 1
    • 2
  • Mingfeng Shao
    • 1
  • Taijin Wang
    • 1
  • Tingxuan Lan
    • 1
  • Chufeng Zhang
    • 1
  • Lijuan Chen
    • 1
  1. 1.Cancer Center, West China HospitalSichuan University and Collaborative Innovation CenterChengduPeople’s Republic of China
  2. 2.Department of Pharmacology, School of PharmacyGuangxi Medical UniversityNanningPeople’s Republic of China

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