Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery.

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.

• Authors: Stephan G Zech, Anna Kohlmann, Tianjun Zhou, Feng Li, Rachel M Squillace, Lois E Parillon, Matthew T Greenfield, David P Miller, Jiwei Qi, R Mathew Thomas, Yihan Wang, Yongjin Xu, Juan J Miret, William C Shakespeare, Xiaotian Zhu, David C Dalgarno
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 2 Pg. 671-86 (Jan 28 2016) ISSN: 1520-4804 [Electronic] United States
• PMID: 26700752 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Small Molecule Libraries
• Phosphorylcholine
• CHKA protein, human
• Choline Kinase

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Choline Kinase (antagonists & inhibitors, isolation & purification)
• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Drug Discovery (methods)
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• High-Throughput Screening Assays
• Humans
• Models, Molecular
• Phosphorylcholine (metabolism)
• Protein Binding
• Small Molecule Libraries