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]- 详细信息    查看全文

• 作者：Anna Tochowicz ; Sean Dalziel ; Oliv Eidam ; Joseph D. O鈥機onnell ; III ; Sarah Griner ; Janet S. Finer-Moore ; Robert M. Stroud
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5446-5455
• 全文大小：565K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

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-纬-glutamyl-d-glutamic acid <b>1b> (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 伪-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through 伪-folate receptor (伪-FR) transport. The 伪-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for <b>1b> similar to that for its natural ligand, folic acid. This study describes a novel synthesis of <b>1b>, an X-ray crystal structure of its complex with Escherichia coli TS and 2鈥?deoxyuridine-5鈥?monophosphate, and a model for a similar complex with human TS.