6FIL

DDR1, 2-[8-(1H-indazole-5-carbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-methylacetamide, 1.730A, P212121, Rfree=24.5%

Summary for 6FIL

• Entry DOI: 10.2210/pdb6fil/pdb
• Related: 6fer 6few 6fex
• Descriptor: Epithelial discoidin domain-containing receptor 1, 2-[8-(2~{H}-indazol-5-ylcarbonyl)-4-oxidanylidene-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-~{N}-methyl-ethanamide, IODIDE ION, ... (4 entities in total)
• Functional Keywords: rtk, receptor tyrosine kinase, collagen, discoidin domain;, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37076.26

Authors

Stihle, M.,Richter, H.,Benz, J.,Kuhn, B.,Rudolph, M.G. (deposition date: 2018-01-19, release date: 2018-11-28, Last modification date: 2024-05-01)

Primary citation

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.,Kim, J.J.,Santos, J.V.,Stihle, M.,Georges, G.J.,Bonfil, R.D.,Fridman, R.,Uhles, S.,Moll, S.,Faul, C.,Fornoni, A.,Prunotto, M.
DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome.
Acs Chem.Biol., 14:37-49, 2019

PubMed 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.

PubMed: 30452219
DOI: 10.1021/acschembio.8b00866

Experimental method

X-RAY DIFFRACTION (1.73 Å)