3M11

Crystal Structure of Aurora A Kinase complexed with inhibitor

3M11 の概要

• エントリーDOI: 10.2210/pdb3m11/pdb
• 分子名称: Serine/threonine-protein kinase 6, 1-(4-{2-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl}phenyl)-3-phenylurea (3 entities in total)
• 機能のキーワード: aurora kinase inhibitor, x-ray co-crystal analysis, structure-based drug design, atp-binding, cell cycle, cytoskeleton, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32884.72

構造登録者

Wu, J.S.,Leou, J.S.,Coumar, M.S.,Hsieh, H.P.,Wu, S.Y. (登録日: 2010-03-03, 公開日: 2011-03-09, 最終更新日: 2023-11-01)

主引用文献

Coumar, M.S.,Chu, C.Y.,Lin, C.W.,Shiao, H.Y.,Ho, Y.L.,Reddy, R.,Lin, W.H.,Chen, C.H.,Peng, Y.H.,Leou, J.S.,Lien, T.W.,Huang, C.T.,Fang, M.Y.,Wu, S.H.,Wu, J.S.,Chittimalla, S.K.,Song, J.S.,Hsu, J.T.,Wu, S.Y.,Liao, C.C.,Chao, Y.S.,Hsieh, H.P.
Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification
J.Med.Chem., 53:4980-4988, 2010

PubMed Abstract: A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

PubMed: 20550212
DOI: 10.1021/jm1000198

実験手法

X-RAY DIFFRACTION (2.75 Å)