5IHC

MELK in complex with NVS-MELK12B

5IHC の概要

• エントリーDOI: 10.2210/pdb5ihc/pdb
• 関連するPDBエントリー: 5HI8 5HI9 5IHA
• 分子名称: Maternal embryonic leucine zipper kinase, 4-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]-3-[(piperidin-4-yl)methoxy]pyridine (3 entities in total)
• 機能のキーワード: kinase uba domain inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Peripheral membrane protein : Q14680
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39311.49

構造登録者

Sprague, E.R.,Brazell, T. (登録日: 2016-02-29, 公開日: 2016-06-01, 最終更新日: 2024-03-06)

主引用文献

Toure, B.B.,Giraldes, J.,Smith, T.,Sprague, E.R.,Wang, Y.,Mathieu, S.,Chen, Z.,Mishina, Y.,Feng, Y.,Yan-Neale, Y.,Shakya, S.,Chen, D.,Meyer, M.,Puleo, D.,Brazell, J.T.,Straub, C.,Sage, D.,Wright, K.,Yuan, Y.,Chen, X.,Duca, J.,Kim, S.,Tian, L.,Martin, E.,Hurov, K.,Shao, W.
Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight.
J.Med.Chem., 59:4711-4723, 2016

PubMed Abstract: MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

PubMed: 27187609
DOI: 10.1021/acs.jmedchem.6b00052

実験手法

X-RAY DIFFRACTION (2.14 Å)