3TCP

Crystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC569

3TCP の概要

• エントリーDOI: 10.2210/pdb3tcp/pdb
• 関連するPDBエントリー: 2BRB 2POC 3BPR
• 分子名称: Tyrosine-protein kinase Mer, 1-[(trans-4-aminocyclohexyl)methyl]-N-butyl-3-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine, CHLORIDE 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: 72798.47

構造登録者

Liu, J.,Yang, C.,Simpson, C.,DeRyckere, D.,Van Deusen, A.,Miley, M.,Kireev, D.B.,Norris-Drouin, J.,Sather, S.,Hunter, D.,Patel, H.S.,Janzen, W.P.,Machius, M.,Johnson, G.,Earp, H.S.,Graham, D.K.,Frye, S.,Wang, X. (登録日: 2011-08-09, 公開日: 2012-06-20, 最終更新日: 2023-09-13)

主引用文献

Liu, J.,Yang, C.,Simpson, C.,Deryckere, D.,Van Deusen, A.,Miley, M.J.,Kireev, D.,Norris-Drouin, J.,Sather, S.,Hunter, D.,Korboukh, V.K.,Patel, H.S.,Janzen, W.P.,Machius, M.,Johnson, G.L.,Earp, H.S.,Graham, D.K.,Frye, S.V.,Wang, X.
Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia.
ACS Med Chem Lett, 3:129-134, 2012

PubMed Abstract: Ectopic Mer expression promotes pro-survival signaling and contributes to leukemogenesis and chemoresistance in childhood acute lymphoblastic leukemia (ALL). Consequently, Mer kinase inhibitors may promote leukemic cell death and further act as chemosensitizers increasing efficacy and reducing toxicities of current ALL regimens. We have applied a structure-based design approach to discover novel small molecule Mer kinase inhibitors. Several pyrazolopyrimidine derivatives effectively inhibit Mer kinase activity at sub-nanomolar concentrations. Furthermore, the lead compound shows a promising selectivity profile against a panel of 72 kinases and has excellent pharmacokinetic properties. We also describe the crystal structure of the complex between the lead compound and Mer, opening new opportunities for further optimization and new template design.

PubMed: 22662287

実験手法

X-RAY DIFFRACTION (2.69 Å)