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 Kim; Javier Varona Santos; Martine Stihle; Guy J. Georges; R. Daniel Bonfil; Rafael Fridman; Sabine Uhles; Solange Moll; Christian Faul; Alessia Fornoni; Marco Prunotto
ACS Chem. Biol., 2019, 14, 1, 37-49
https://doi.org/10.1021/acschembio.8b00866

Abstract

The importance of 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.