5EQE

Crystal structure of choline kinase alpha-1 bound by [4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]methanamine (compound 11)

5EQE の概要

• エントリーDOI: 10.2210/pdb5eqe/pdb
• 関連するPDBエントリー: 5EQP 5EQY
• 分子名称: Choline kinase alpha, [4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]methanamine (3 entities in total)
• 機能のキーワード: kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P35790
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 94179.66

構造登録者

Zhou, T.,Zhu, X.,Dalgarno, D.C. (登録日: 2015-11-12, 公開日: 2016-01-06, 最終更新日: 2024-03-06)

主引用文献

Zech, S.G.,Kohlmann, A.,Zhou, T.,Li, F.,Squillace, R.M.,Parillon, L.E.,Greenfield, M.T.,Miller, D.P.,Qi, J.,Thomas, R.M.,Wang, Y.,Xu, Y.,Miret, J.J.,Shakespeare, W.C.,Zhu, X.,Dalgarno, D.C.
Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery.
J.Med.Chem., 59:671-686, 2016

PubMed Abstract: Choline kinase α (ChoKα) is an enzyme involved in the synthesis of phospholipids and thereby plays key roles in regulation of cell proliferation, oncogenic transformation, and human carcinogenesis. Since several inhibitors of ChoKα display antiproliferative activity in both cellular and animal models, this novel oncogene has recently gained interest as a promising small molecule target for cancer therapy. Here we summarize our efforts to further validate ChoKα as an oncogenic target and explore the activity of novel small molecule inhibitors of ChoKα. Starting from weakly binding fragments, we describe a structure based lead discovery approach, which resulted in novel highly potent inhibitors of ChoKα. In cancer cell lines, our lead compounds exhibit a dose-dependent decrease of phosphocholine, inhibition of cell growth, and induction of apoptosis at low micromolar concentrations. The druglike lead series presented here is optimizable for improvements in cellular potency, drug target residence time, and pharmacokinetic parameters. These inhibitors may be utilized not only to further validate ChoKα as antioncogenic target but also as novel chemical matter that may lead to antitumor agents that specifically interfere with cancer cell metabolism.

PubMed: 26700752
DOI: 10.1021/acs.jmedchem.5b01552

実験手法

X-RAY DIFFRACTION (2.4 Å)