RT Journal Article
SR Electronic
T1 Structure of the complex of an iminopyridinedione PTP4A3 phosphatase inhibitor with human serum albumin
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP MOLPHARM-AR-2020-000131
DO 10.1124/molpharm.120.000131
A1 Mateusz P. Czub
A1 Adam M. Boulton
A1 Ettore J. Rastelli
A1 Nikhil R. Tasker
A1 Taber S. Maskrey
A1 Isabella K. Blanco
A1 Kelley E. McQueeney
A1 John H. Bushweller
A1 Wladek Minor
A1 Peter Wipf
A1 Elizabeth R. Sharlow
A1 John S. Lazo
YR 2020
UL http://molpharm.aspetjournals.org/content/early/2020/09/25/molpharm.120.000131.abstract
AB Protein tyrosine phosphatase 4A3 (PTP4A3) is frequently overexpressed in human solid tumors and hematological malignancies and is associated with tumor cell invasion, metastasis, and a poor patient prognosis. Several potent, selective, and allosteric small molecule inhibitors of PTP4A3 were recently identified. A lead compound in the series, JMS-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), has a long plasma half-life (t1/2 ~24 h) in mice, suggesting possible binding to serum components. We confirmed by isothermal titration calorimetry that JMS-053 binds to human serum albumin. A single JMS-053 binding site was identified by X-ray crystallography in human serum albumin drug at site 3, which is also known as subdomain IB. The binding of JMS-053 to human serum albumin, however, did not markedly alter the overall albumin structure. In the presence of serum albumin, the potency of JMS-053 as an in vitro inhibitor of PTP4A3 and human A2780 ovarian cancer cell growth was reduced. The reversible binding of JMS-053 to serum albumin may serve to increase JMS-053's plasma half-life and thus extend the delivery of the compound to tumors. Significance Statement X-ray crystallography revealed that a potent, reversible, first-in-class small molecule inhibitor of the oncogenic phosphatase PTP4A3 binds to at least one-site on human serum albumin, which is likely to extend the compound’s plasma half-life and thus assist in drug delivery into tumors.