4ISK

Crystal structure of E.coli thymidylate synthase with dUMP and the BGC 945 inhibitor

Summary for 4ISK

• Entry DOI: 10.2210/pdb4isk/pdb
• Related: 1AN5 1AXW 1HVY 2KCE
• Descriptor: Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: alpha/beta protein, methylase, methyltransferase, dump subtrate, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli
• Cellular location: Cytoplasm: P0A884
• Total number of polymer chains: 8
• Total formula weight: 252304.06

Authors

Tochowicz, A.,Finer-Moore, J.,Stroud, R.M. (deposition date: 2013-01-16, release date: 2013-12-25, Last modification date: 2024-11-27)

Primary citation

Tochowicz, A.,Dalziel, S.,Eidam, O.,O'Connell, J.D.,Griner, S.,Finer-Moore, J.S.,Stroud, R.M.
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-gamma-glutamyl-d-glutamic Acid (BGC 945), a Novel Thymidylate Synthase Inhibitor That Targets Tumor Cells.
J.Med.Chem., 56:5446-5455, 2013

PubMed 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.

PubMed: 23710599
DOI: 10.1021/jm400490e

Experimental method

X-RAY DIFFRACTION (1.752 Å)