2. Academic Validation
  3. Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe

Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe

  • J Med Chem. 2021 Sep 23;64(18):13451-13474. doi: 10.1021/acs.jmedchem.1c00868.
Sandra Röhm 1 2,  Benedict-Tilman Berger 1 2,  Martin Schröder 1 2,  Deep Chatterjee 1 2,  Sebastian Mathea 1 2,  Andreas C Joerger 1 2,  Daniel M Pinkas 3,  Joshua C Bufton 3,  Amelie Tjaden 1 2,  Lohitesh Kovooru 2 4,  Mark Kudolo 5,  Christian Pohl 2 4,  Alex N Bullock 3,  Susanne Müller 1 2,  Stefan Laufer 5,  Stefan Knapp 1 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3 Centre for Medicines Discovery, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 4 Institute of Biochemistry II, Faculty of Medicine, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 5 Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
PMID: 34506142 DOI: 10.1021/acs.jmedchem.1c00868
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.

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