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

  • ACS Chem Biol. 2019 Jan 18;14(1):37-49. doi: 10.1021/acschembio.8b00866.
Hans Richter  1 ,  Alexander L Satz  1 ,  Marc Bedoucha  1 ,  Bernd Buettelmann  1 ,  Ann C Petersen  1 ,  Anja Harmeier  1 ,  Ricardo Hermosilla  1 ,  Remo Hochstrasser  1 ,  Dominique Burger  1 ,  Bernard Gsell  1 ,  Rodolfo Gasser  1 ,  Sylwia Huber  1 ,  Melanie N Hug  1 ,  Buelent Kocer  1 ,  Bernd Kuhn  1 ,  Martin Ritter  1 ,  Markus G Rudolph  1 ,  Franziska Weibel  1  2 ,  Judith Molina-David  3  4 ,  Jin-Ju Kim  3  4 ,  Javier Varona Santos  3  4 ,  Martine Stihle  1 ,  Guy J Georges  5 ,  R Daniel Bonfil  6 ,  Rafael Fridman  7 ,  Sabine Uhles  1 ,  Solange Moll  8 ,  Christian Faul  9 ,  Alessia Fornoni  3 ,  Marco Prunotto  1  10
Affiliations
  • 1. Roche Pharma Research and Early Development, Roche Innovation Center , Basel 4070 , Switzerland.
  • 2. Ridgeline Therapeutics GmbH , Basel 4070 , Switzerland.
  • 3. Katz Family Division of Nephrology and Hypertension , University of Miami Miller School of Medicine , Miami , Florida 33136 , United States.
  • 4. Peggy and Harold Katz Family Drug Discovery Center , University of Miami Miller School of Medicine , Miami , Florida 33136 , United States.
  • 5. Roche Pharma Research and Early Development, Roche Innovation Center , Munich 82377 , Germany.
  • 6. Department of Pathology, College of Medical Sciences , Nova Southeastern University , Fort Lauderdale , Florida 33328 , United States.
  • 7. Department of Pathology , Wayne State University , Detroit , Michigan 48202 , United States.
  • 8. University Hospital of Geneva , 1205 Geneva , Switzerland.
  • 9. University of Alabama at Birmingham , Birmingham , Alabama 35294, United States.
  • 10. Office of Innovation, Immunology, Infectious Diseases & Ophthalmology (I2O) , Roche and Genentech Late Stage Development , Basel 4070 , Switzerland.
PMID: 30452219 DOI: 10.1021/acschembio.8b00866
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.

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