2. Academic Validation
  3. Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

  • J Med Chem. 2023 Oct 12;66(19):13400-13415. doi: 10.1021/acs.jmedchem.3c00554.
Magnus Nilsson 1,  Kristina Berggren 1,  Susanne Berglund 1,  Silvia Cerboni 2,  Mia Collins 2,  Göran Dahl 3,  David Elmqvist 4,  Neil P Grimster 5,  Ramon Hendrickx 6,  Johan R Johansson 1,  Jason G Kettle 5,  Matti Lepistö 1,  Magdalena Rhedin 2,  Amir Smailagic 2,  Qibin Su 5,  Tiiu Wennberg 2,  Allan Wu 7,  Torben Österlund 8,  Thomas Naessens 2,  Suman Mitra 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 2 Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 3 Structure and Biophysics, Research and Early Development, Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 4 Early Product Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 5 Oncology R&D, AstraZeneca R&D, Waltham, Massachusetts 02451, United States.
  • 6 DMPK, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
  • 7 Discovery Sciences, R&D, AstraZeneca R&D, Waltham, Massachusetts 02451, United States.
  • 8 Mechanistic Biology & Profiling, Research and Early Development, Discovery Science, BioPharmaceuticals R&D, AstraZeneca, Gothenburg SE-431 83, Sweden.
PMID: 37738648 DOI: 10.1021/acs.jmedchem.3c00554
Abstract

JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.

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