5EQY

Crystal structure of choline kinase alpha-1 bound by 5-[(4-methyl-1,4-diazepan-1-yl)methyl]-2-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]benzenecarbonitrile (compound 65)

Summary for 5EQY

• Entry DOI: 10.2210/pdb5eqy/pdb
• Related: 5EQE 5EQP
• Descriptor: Choline kinase alpha, 5-[(4-methyl-1,4-diazepan-1-yl)methyl]-2-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]benzenecarbonitrile (3 entities in total)
• Functional Keywords: kinase, inhibitor, drug target, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P35790
• Total number of polymer chains: 2
• Total formula weight: 94576.19

Authors

Zhou, T.,Zhu, X.,Dalgarno, D.C. (deposition date: 2015-11-13, release date: 2016-01-06, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)