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

• Published in: Journal of medicinal chemistry 2013-07, Vol.56 (13), p.5446-5455
• Main Authors: Tochowicz, Anna, Dalziel, Sean, Eidam, Oliv, O’Connell, Joseph D, Griner, Sarah, Finer-Moore, Janet S, Stroud, Robert M
• Format: Article
• Language: English
• Subjects: Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Escherichia coli - enzymology; Escherichia coli Proteins - antagonists & inhibitors; Escherichia coli Proteins - chemistry; Escherichia coli Proteins - metabolism; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - metabolism; Folic Acid Antagonists - pharmacology; Humans; Models, Chemical; Models, Molecular; Molecular Structure; Neoplasms - enzymology; Neoplasms - pathology; Protein Binding; Protein Structure, Tertiary; Quinazolines - chemical synthesis; Quinazolines - metabolism; Quinazolines - pharmacology; Thymidylate Synthase - antagonists & inhibitors; Thymidylate Synthase - chemistry; Thymidylate Synthase - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400490e

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.