6GWR

Structure of the kinase domain of human DDR1 in complex with a potent and selective inhibitor of DDR1 and DDR2

Summary for 6GWR

• Entry DOI: 10.2210/pdb6gwr/pdb
• Descriptor: Epithelial discoidin domain-containing receptor 1, 3-(2-imidazo[1,2-a]pyrazin-3-ylethynyl)-~{N}-[3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)phenyl]-4-propan-2-yl-benzamide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 74136.81

Authors

Pinkas, D.M.,Fox, A.E.,Kupinska, K.,Burgess-Brown, N.A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N. (deposition date: 2018-06-25, release date: 2018-08-08, Last modification date: 2024-05-15)

Primary citation

Wang, Z.,Zhang, Y.,Pinkas, D.M.,Fox, A.E.,Luo, J.,Huang, H.,Cui, S.,Xiang, Q.,Xu, T.,Xun, Q.,Zhu, D.,Tu, Z.,Ren, X.,Brekken, R.A.,Bullock, A.N.,Liang, G.,Ding, K.,Lu, X.
Design, Synthesis, and Biological Evaluation of 3-(Imidazo[1,2- a]pyrazin-3-ylethynyl)-4-isopropyl- N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide as a Dual Inhibitor of Discoidin Domain Receptors 1 and 2.
J. Med. Chem., 61:7977-7990, 2018

PubMed Abstract: Discoidin-domain receptors 1 and 2 (DDR1 and DDR2) are new potential targets for anti-inflammatory-drug discovery. A series of heterocycloalkynylbenzimides were designed and optimized to coinhibit DDR1 and DDR2. One of the most promising compounds, 5n, tightly bound to DDR1 and DDR2 proteins with K values of 7.9 and 8.0 nM; potently inhibited the kinases with IC values of 9.4 and 20.4 nM, respectively; and was significantly less potent for a panel of 403 wild-type kinases at 1.0 μM. DDR1- and DDR2-kinase inhibition by 5n was validated by Western-blotting analysis in primary human lung fibroblasts. The compound also dose-dependently inhibited lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release in vitro and exhibited promising in vivo anti-inflammatory effects in an LPS-induced-acute-lung-injury (ALI) mouse model. Compound 5n may serve as a lead compound for new anti-inflammatory drug discovery.

PubMed: 30075624
DOI: 10.1021/acs.jmedchem.8b01045

Experimental method

X-RAY DIFFRACTION (2.07 Å)