TY - JOUR T1 - Structure of the complex of an iminopyridinedione PTP4A3 phosphatase inhibitor with human serum albumin JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.120.000131 SP - MOLPHARM-AR-2020-000131 AU - Mateusz P. Czub AU - Adam M. Boulton AU - Ettore J. Rastelli AU - Nikhil R. Tasker AU - Taber S. Maskrey AU - Isabella K. Blanco AU - Kelley E. McQueeney AU - John H. Bushweller AU - Wladek Minor AU - Peter Wipf AU - Elizabeth R. Sharlow AU - John S. Lazo Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/09/25/molpharm.120.000131.abstract N2 - 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. ER -