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DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome

Richter, Hans
Satz, Alexander L
Bedoucha, Marc
Buettelmann, Bernd
Petersen, Ann C
Harmeier, Anja
Hermosilla, Ricardo
Hochstrasser, Remo
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Published in ACS Chemical Biology. 2019, vol. 14, no. 1, p. 37-49
Abstract 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.
PMID: 30452219
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Article (Published version) (4.9 MB) - public document Free access
Research group Analyse protéomique et Analyse génomique des maladies rénales (659)
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RICHTER, Hans et al. DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome. In: ACS Chemical Biology, 2019, vol. 14, n° 1, p. 37-49. doi: 10.1021/acschembio.8b00866 https://archive-ouverte.unige.ch/unige:120175

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Deposited on : 2019-06-28

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