DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome
| Autor: | Bernd Kuhn, Franziska Weibel, Rodolfo Gasser, Marco Prunotto, Solange Moll, Martine Stihle, R. Daniel Bonfil, Bernard Gsell, Christian Faul, Remo Hochstrasser, Sabine Uhles, Guy Georges, Ann C. Petersen, Javier Varona Santos, Ricardo Hermosilla, Alexander L. Satz, Hans Richter, Rafael Fridman, Marc Bedoucha, Markus G. Rudolph, Bernd Buettelmann, Anja Harmeier, Martin Ritter, Melanie N. Hug, Alessia Fornoni, Judith Molina-David, Jin Ju Kim, Sylwia Huber, Buelent Kocer, Dominique Burger |
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| Rok vydání: | 2018 |
| Předmět: |
Collagen Type IV
0301 basic medicine Src Homology 2 Domain-Containing Transforming Protein 1 Nephritis Hereditary ddc:616.07 Kidney Kidney Function Tests Autoantigens 01 natural sciences Biochemistry Mice 03 medical and health sciences Discoidin Domain Receptor 1 In vivo Renal fibrosis Animals Kinome Phosphorylation Receptor Gene knockout Mice Knockout DDR1 010405 organic chemistry Chemistry Epithelial Cells Articles DNA General Medicine 0104 chemical sciences Cell biology Disease Models Animal 030104 developmental biology Molecular Medicine Discoidin domain |
| Zdroj: | ACS Chemical Biology ACS Chemical Biology, Vol. 14, No 1 (2019) pp. 37-49 |
| ISSN: | 1554-8937 1554-8929 |
| Popis: | The importance of Discoidin Domain Receptor 1 (DDR1) in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein, while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population. |
| Databáze: | OpenAIRE |
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