Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery
| Autor: | Stephan G. Zech, Feng Li, Rachel M. Squillace, R. Mathew Thomas, David C. Dalgarno, David Miller, Yihan Wang, Matthew T. Greenfield, Xiaotian Zhu, William C. Shakespeare, Yongjin Xu, Jiwei Qi, Lois Parillon, Tianjun Zhou, Anna Kohlmann, Juan J. Miret |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Models Molecular Choline kinase Phosphorylcholine Fragment-based lead discovery Antineoplastic Agents Apoptosis medicine.disease_cause Crystallography X-Ray Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Drug Discovery medicine Choline Kinase Humans Enzyme Inhibitors Phosphocholine Cell Proliferation chemistry.chemical_classification Oncogene Dose-Response Relationship Drug Cell growth Small molecule High-Throughput Screening Assays 030104 developmental biology Enzyme chemistry Biochemistry 030220 oncology & carcinogenesis Molecular Medicine Carcinogenesis Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 59(2) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|