Development of a selective dual discoidin domain receptor (DDR)/p38 kinase chemical probe

DOI: 10.1021/acs.jmedchem.1c00868

Authors: Sandra Röhm (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Benedict-Tilman Berger (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Martin Schröder (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Deep Chatterjee (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Sebastian Mathea (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Andreas C. Joerger (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Daniel M. Pinkas (University of Oxford) , Joshua C. Bufton (University of Oxford) , Amelie Tjaden (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Lohitesh Kovooru (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Mark Kudolo (Eberhard Karls University Tübingen) , Christian Pohl (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Alex N. Bullock (University of Oxford) , Susanne Müller (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences) , Stefan Laufer (Eberhard Karls University Tübingen) , Stefan Knapp (Johann Wolfgang Goethe University; Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 64 , PAGES 13451 - 13474

State: Published (Approved)
Published: September 2021

Abstract: Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal and pulmonary fibrosis, atherosclerosis, and various forms of cancer. Potent and selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases such as the tyrosine protein kinase receptor TIE or tropomyosin receptor kinases, which are related to angiogenesis and neuronal toxicity. In this study, we optimized our recently published p38 mitogen-activated protein kinase inhibitor 7 toward a potent and cell-active dual DDR/p38 chemical probe and developed a structurally related negative control. The structure-guided design approach used provided insights into the P-loop folding process of p38 and how targeting of non-conserved amino acids modulates inhibitor selectivity. The developed and comprehensively characterized DDR/p38 probe, 30 (SR-302), is a valuable tool for studying the role of DDR kinase in normal physiology and in disease development.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: 14.1 at BESSY; X06SA at SLS

Added On: 15/09/2022 15:14

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)