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

J Med Chem. 2013 Jul 11;56(13):5446-55. doi: 10.1021/jm400490e. Epub 2013 Jun 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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

Substances

  • BGC945
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Folic Acid Antagonists
  • Quinazolines
  • Thymidylate Synthase

Associated data

  • PDB/4ISK