IngentaConnect New targets for an old drug: II. Hypoxanthine-guanine amidophosph...

Authors: Slon-Usakiewicz, Jacek¹; Pasternak, Andrew²; Reid, Neil²; Toledo-Sherman, Leticia²

Source: Clinical Proteomics, Volume 1, Numbers 3-4, September 2004 , pp. 227-234(8)

Abstract:

Methotrexate has been a clinical agent used in cancer, immunosuppression, rheumatoid arthritis, and other highly proliferative diseases for many years, yet its underlying molecular mechanism of action in these therapeutic areas is still unclear. We have previously reported using a chemical proteomics technique on several other potential pharmacodynamic targets of methotrexate. Here, using a frontal affinity chromatography with mass spectrometry detection, we confirm one of these targets, hypoxanthine-guanine amidophosphoribosyltransferase, as a true binder of methotrexate with a K_d of 4.2 μM. These results complement and confirm our recent study, but more importantly, shed light into the mechanism of action of methotrexate in oncology and other highly proliferative diseases and may help explain some unaccounted for effects of this drug. For example, despite the fact that DNA salvage pathway enzymes are highly active, methotrexate can be effective if it only targets enzymes of the de novo pathway.

Keywords: Methotrexate; HGPRT; chemical; proteomics; mechanism of action

Document Type: Research article

DOI: 10.1385/CP:1:3-4:227

Affiliations: 1: OptiMol Drug Discovery Division, Protana Inc., 251 Attwell Drive, M9W 7H4, Toronto, ON, Canada, Email: jslon@protana.com 2: OptiMol Drug Discovery Division, Protana Inc., 251 Attwell Drive, M9W 7H4, Toronto, ON, Canada,

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New targets for an old drug: II. Hypoxanthine-guanine amidophosphoribosyltransferase as a new pharmacodynamic target of methotrexate