Development and binding mode assessment of N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-D-glutamic acid (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells
| Autor: | Tochowicz, Anna, Dalziel, Sean, Eidam, Oliv, O'Connell, Joseph D, Griner, Sarah, Finer-Moore, Janet S, Stroud, Robert M |
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| Rok vydání: | 2013 |
| Předmět: |
Protein Structure
Medicinal & Biomolecular Chemistry Chemical Medicinal and Biomolecular Chemistry Rare Diseases Models Neoplasms Escherichia coli Humans Enzyme Inhibitors Cancer Crystallography Molecular Structure Escherichia coli Proteins Organic Chemistry Molecular Thymidylate Synthase Pharmacology and Pharmaceutical Sciences Orphan Drug 5.1 Pharmaceuticals Drug Design Quinazolines X-Ray Folic Acid Antagonists Development of treatments and therapeutic interventions Tertiary Protein Binding |
| Zdroj: | Journal of medicinal chemistry, vol 56, iss 13 |
| Popis: | N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic acid 1 (BGC 945, now known as ONX 0801), is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase 1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with α-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through α-folate receptor (α-FR) transport. The α-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS. |
| Databáze: | OpenAIRE |
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