5BVW

Fragment-based discovery of potent and selective DDR1/2 inhibitors

Summary for 5BVW

• Entry DOI: 10.2210/pdb5bvw/pdb
• Descriptor: Epithelial discoidin domain-containing receptor 1, IODIDE ION, N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE, ... (4 entities in total)
• Functional Keywords: ddr1, fragments, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cell membrane; Single-pass type I membrane protein. Isoform 3: Secreted . Isoform 4: Cell membrane; Single-pass type I membrane protein: Q08345
• Total number of polymer chains: 1
• Total formula weight: 37939.02

Authors

Murray, C.,Berdini, V.,Buck, I.,Carr, M.,Cleasby, A.,Coyle, J.,Curry, J.,Day, J.,Hearn, K.,Iqbal, A.,Lee, L.,Martins, V.,Mortenson, P.,Munck, J.,Page, L.,Patel, S.,Roomans, S.,Kirsten, T.,Saxty, G. (deposition date: 2015-06-05, release date: 2015-08-05)

Primary citation

Murray, C.W.,Berdini, V.,Buck, I.M.,Carr, M.E.,Cleasby, A.,Coyle, J.E.,Curry, J.E.,Day, J.E.,Day, P.J.,Hearn, K.,Iqbal, A.,Lee, L.Y.,Martins, V.,Mortenson, P.N.,Munck, J.M.,Page, L.W.,Patel, S.,Roomans, S.,Smith, K.,Tamanini, E.,Saxty, G.
Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.
Acs Med.Chem.Lett., 6:798-803, 2015

PubMed Abstract: The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

PubMed: 26191369
DOI: 10.1021/acsmedchemlett.5b00143

Experimental method

X-RAY DIFFRACTION (1.94 Å)