4MH7

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC1896

4MH7 の概要

• エントリーDOI: 10.2210/pdb4mh7/pdb
• 関連するPDBエントリー: 2BRB 2POC 3BPR 3TCP 4M3Q 4MHA
• 分子名称: Tyrosine-protein kinase Mer, CHLORIDE ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: tyrosine kinase, acute lymphoblastic leukemia, rational structure based drug design, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane ; Single-pass type I membrane protein : Q12866
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72488.63

構造登録者

Zhang, W.,McIver, A.,Stashko, M.A.,Deryckere, D.,Branchford, B.R.,Hunter, D.,Kireev, D.B.,Miley, M.J.,Norris-Drouin, J.,Stewart, W.M.,Lee, M.,Sather, S.,Zhou, Y.,DiPaola, J.A.,Machius, M.,Janzen, W.P.,Earp, H.S.,Graham, D.K.,Frye, S.,Wang, X. (登録日: 2013-08-29, 公開日: 2014-05-21, 最終更新日: 2023-09-20)

主引用文献

Zhang, W.,McIver, A.L.,Stashko, M.A.,DeRyckere, D.,Branchford, B.R.,Hunter, D.,Kireev, D.,Miley, M.J.,Norris-Drouin, J.,Stewart, W.M.,Lee, M.,Sather, S.,Zhou, Y.,Di Paola, J.A.,Machius, M.,Janzen, W.P.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.
Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis.
J.Med.Chem., 56:9693-9700, 2013

PubMed Abstract: The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

PubMed: 24219778
DOI: 10.1021/jm4013888

実験手法

X-RAY DIFFRACTION (2.51 Å)