5BVK

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

5BVK の概要

• エントリーDOI: 10.2210/pdb5bvk/pdb
• 分子名称: Epithelial discoidin domain-containing receptor 1, IODIDE ION, 1-(2-chlorophenyl)-3-(pyridin-3-ylmethyl)urea, ... (4 entities in total)
• 機能のキーワード: ddr1, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: 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
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37458.92

構造登録者

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. (登録日: 2015-06-05, 公開日: 2015-08-05, 最終更新日: 2024-05-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.29 Å)