Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 12, Pages 5350-5366Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00571
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Funding
- DFG Sonderforschungsbereich [SFB1177]
- DFG [FOR 2497/TP02]
- SGC [1097737]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Centre of Excellence Macromolecular Complexes (CEF) at Frankfurt University
- German Cancer network DKTK
- Recruitment of Excellent Junior Researchers Grant of the University of Tubingen
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Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable colocalization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein, we describe detailed structure-activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity, and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.
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