| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 10593490 | Bioorganic & Medicinal Chemistry Letters | 2012 | 4 Pages |
Abstract
Cancer cells isolated from two patients with malignant non-Hodgkin B-cell lymphomas that became resistant to chemotherapy during clinical treatment were made ⩾fourfold resistant in culture to anticancer drugs, that is cisplatin, etoposide, methotrexate and bortezomib. Because most resistant lines showed significantly increased expression of the anti-oxidative enzyme glutathione peroxidase 1 (GPx1), GPx1 was investigated as a target for inhibitor development. Virtual screening of a library of diverse structures by docking them to the active site of the X-ray crystal structure of bovine GPx1 uncovered compounds that might block the enzyme. An enzyme assay confirmed an acylhydrazone heterocycle (3) with GPx inhibitory activity. Combinations of 3 with the anticancer drugs listed above led to reversal of resistance in the lymphoma cell lines.
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Authors
Riad Schulz, Thomas Emmrich, Heidi Lemmerhirt, Ulrike Leffler, Kristin Sydow, Carsten Hirt, Thomas Kiefer, Andreas Link, Patrick J. Bednarski,