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Development, optimization and structure–activity relationships of covalent-reversible JAK3 inhibitors based on a tricyclic imidazo[5,4-d]pyrrolo[2,3-b]pyridine scaffold
DOI:
10.1021/acs.jmedchem.8b00571
Authors:
Michael
Forster
(Eberhard Karls University Tübingen)
,
Apirat
Chaikuad
(Structure Genomics Consortium, Johann Wolfgang Goethe University)
,
Teodor
Dimitrov
(Eberhard Karls University Tübingen)
,
Eva
Döring
(Eberhard Karls University Tübingen)
,
Julia
Holstein
(Eberhard Karls University Tübingen)
,
Benedict-Tilman
Berger
(Structure Genomics Consortium, Johann Wolfgang Goethe University)
,
Matthias
Gehringer
(Eberhard Karls University Tübingen)
,
Kamran
Ghoreschi
(Eberhard Karls University Tübingen)
,
Susanne
Müller
(Johann Wolfgang Goethe University)
,
Stefan
Knapp
(Structure Genomics Consortium, Johann Wolfgang Goethe University; German Cancer Consortium (DKTK))
,
Stefan A.
Laufer
(Eberhard Karls University Tübingen)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
State:
Published (Approved)
Published:
May 2018
Diamond Proposal Number(s):
10619
Abstract: 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 co-localization 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.
Journal Keywords: Janus kinases; kinome selectivity; covalent-reversible inhibitor; inflammation
Subject Areas:
Chemistry,
Medicine,
Biology and Bio-materials
Instruments:
I03-Macromolecular Crystallography
Added On:
06/06/2018 11:13
Discipline Tags:
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)