UNIGE document Scientific Article
previous document  unige:120175  next document
add to browser collection
Title

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

Authors
Richter, Hans
Satz, Alexander L
Bedoucha, Marc
Buettelmann, Bernd
Petersen, Ann C
Harmeier, Anja
Hermosilla, Ricardo
Hochstrasser, Remo
show hidden authors show all authors [1 - 30]
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.
Identifiers
PMID: 30452219
Full text
Article (Published version) (4.9 MB) - public document Free access
Structures
Research group Analyse protéomique et Analyse génomique des maladies rénales (659)
Citation
(ISO format)
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

159 hits

103 downloads

Update

Deposited on : 2019-06-28

Export document
Format :
Citation style :