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Discovery of Pyrazolo[3,4- d ]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Jan 13; Vol. 65 (1), pp. 103-119. Date of Electronic Publication: 2021 Nov 25. - Publication Year :
- 2022
-
Abstract
- Alterations of discoidin domain receptor1 (DDR1) may lead to increased production of inflammatory cytokines, making DDR1 an attractive target for inflammatory bowel disease (IBD) therapy. A scaffold-based molecular design workflow was established and performed by integrating a deep generative model, kinase selectivity screening and molecular docking, leading to a novel DDR1 inhibitor compound 2 , which showed potent DDR1 inhibition profile (IC <subscript>50</subscript> = 10.6 ± 1.9 nM) and excellent selectivity against a panel of 430 kinases ( S (10) = 0.002 at 0.1 μM). Compound 2 potently inhibited the expression of pro-inflammatory cytokines and DDR1 autophosphorylation in cells, and it also demonstrated promising oral therapeutic effect in a dextran sulfate sodium (DSS)-induced mouse colitis model.
- Subjects :
- Animals
Anti-Inflammatory Agents chemistry
Colitis chemically induced
Colitis pathology
Dextran Sulfate toxicity
Drug Screening Assays, Antitumor
Humans
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Molecular Structure
Protein Kinase Inhibitors chemistry
Pyrazolones chemistry
Pyridazines chemistry
Anti-Inflammatory Agents pharmacology
Colitis drug therapy
Deep Learning
Discoidin Domain Receptor 1 antagonists & inhibitors
Drug Design
Drug Discovery
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34821145
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01205