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

Hans Richter, Alexander L. Satz, Marc Bedoucha, Bernd Buettelmann, Ann C. Petersen, Anja Harmeier, Ricardo Hermosilla, Remo Hochstrasser, Dominique Burger, Bernard Gsell, Rodolfo Gasser, Sylwia Huber, Melanie N. Hug, Buelent Kocer, Bernd Kuhn, Martin Ritter, Markus G. Rudolph, Franziska Weibel, Judith Molina-David, Jin Ju KimJavier Varona Santos, Martine Stihle, Guy J. Georges, R. Daniel Bonfil, Rafael Fridman, Sabine Uhles, Solange Moll, Christian Faul, Alessia Fornoni, Marco Prunotto

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37-49
Number of pages13
JournalACS Chemical Biology
Volume14
Issue number1
DOIs
StatePublished - Jan 18 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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    Richter, H., Satz, A. L., Bedoucha, M., Buettelmann, B., Petersen, A. C., Harmeier, A., Hermosilla, R., Hochstrasser, R., Burger, D., Gsell, B., Gasser, R., Huber, S., Hug, M. N., Kocer, B., Kuhn, B., Ritter, M., Rudolph, M. G., Weibel, F., Molina-David, J., ... Prunotto, M. (2019). DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome. ACS Chemical Biology, 14(1), 37-49. https://doi.org/10.1021/acschembio.8b00866