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)