title: 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.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of California-San Francisco , 600 16th Street, San Francisco, California 94158, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Tochowicz
authors.forename: Sean
authors.initials: S
authors.lastname: Dalziel
authors.forename: Oliv
authors.initials: O
authors.lastname: Eidam
authors.forename: Joseph D
authors.initials: JD
authors.lastname: O'Connell
authors.forename: Sarah
authors.initials: S
authors.lastname: Griner
authors.forename: Janet S
authors.initials: JS
authors.lastname: Finer-Moore
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stroud
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: C504662:BGC945; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013940:Thymidylate Synthase