TY - JOUR
T1 - DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome
AU - Richter, Hans
AU - Satz, Alexander L.
AU - Bedoucha, Marc
AU - Buettelmann, Bernd
AU - Petersen, Ann C.
AU - Harmeier, Anja
AU - Hermosilla, Ricardo
AU - Hochstrasser, Remo
AU - Burger, Dominique
AU - Gsell, Bernard
AU - Gasser, Rodolfo
AU - Huber, Sylwia
AU - Hug, Melanie N.
AU - Kocer, Buelent
AU - Kuhn, Bernd
AU - Ritter, Martin
AU - Rudolph, Markus G.
AU - Weibel, Franziska
AU - Molina-David, Judith
AU - Kim, Jin Ju
AU - Santos, Javier Varona
AU - Stihle, Martine
AU - Georges, Guy J.
AU - Bonfil, R. Daniel
AU - Fridman, Rafael
AU - Uhles, Sabine
AU - Moll, Solange
AU - Faul, Christian
AU - Fornoni, Alessia
AU - Prunotto, Marco
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/1/18
Y1 - 2019/1/18
N2 - 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.
AB - 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.
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U2 - 10.1021/acschembio.8b00866
DO - 10.1021/acschembio.8b00866
M3 - Article
C2 - 30452219
AN - SCOPUS:85060140373
VL - 14
SP - 37
EP - 49
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 1
ER -