2. Academic Validation
  3. Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors

Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors

  • J Med Chem. 2018 Jun 28;61(12):5235-5244. doi: 10.1021/acs.jmedchem.8b00076.
Neil P Grimster,  Erica Anderson,  Marat Alimzhanov,  Geraldine Bebernitz,  Kirsten Bell,  Claudio Chuaqui,  Tracy Deegan,  Andrew D Ferguson,  Thomas Gero,  Andreas Harsch,  Dennis Huszar,  Aarti Kawatkar,  Jason G Kettle,  Paul Lyne,  Jon A Read,  Caroline Rivard Costa,  Linette Ruston 1,  Patricia Schroeder,  Jie Shi,  Qibin Su,  Scott Throner,  Dorin Toader,  Melissa Vasbinder,  Richard Woessner,  Haixia Wang,  Allan Wu,  Minwei Ye,  Weijia Zheng,  Michael Zinda
Affiliations

Affiliation

  • 1 Pharmaceutical Sciences, IMED Biotech Unit , AstraZeneca , Macclesfield SK10 2NA , United Kingdom.
PMID: 29856615 DOI: 10.1021/acs.jmedchem.8b00076
Abstract

Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both Cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and Tyk2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 Inhibitor, 24, which displays ∼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112442
    JAK Inhibitor
    JAK