Optimization of a Pipemidic Acid Autotaxin Inhibitor
| Autor: | Daniel L. Baker, Angela L. Howard, Irene W. Wanjala, Heidi E. Bostic, Michael D. Best, Abby L. Parrill, Adrienne B. Hoeglund |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Receptor expression
Drug Evaluation Preclinical Quantitative Structure-Activity Relationship Breast Neoplasms chemistry.chemical_compound Multienzyme Complexes Drug Discovery Lysophosphatidic acid Tumor Cells Cultured medicine Humans Enzyme Inhibitors Pyrophosphatases Enzyme Assays Phosphoric Diester Hydrolases Chemistry Lysophosphatidylcholines Pipemidic acid Ligand (biochemistry) Small molecule Pipemidic Acid Mechanism of action Biochemistry Phosphodiesterase I Alkylglycerophosphoethanolamine phosphodiesterase Computer-Aided Design Molecular Medicine Female lipids (amino acids peptides and proteins) Lysophospholipids Autotaxin medicine.symptom medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 53:1056-1066 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm9012328 |
| Popis: | Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC(50) of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K(i) of 700 nM, making this compound approximately 3-fold more potent than the previously described lead. |
| Databáze: | OpenAIRE |
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