Protein tyrosine phosphatase (PTP) 4A3 is frequently overexpressed in human solid tumors and hematologic 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 (∼ 24 hours) 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 at drug 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.

中文翻译：

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亚氨基吡啶二酮蛋白酪氨酸磷酸酶 4A3 磷酸酶抑制剂与人血清白蛋白复合物的结构

蛋白酪氨酸磷酸酶 (PTP) 4A3 在人类实体瘤和血液系统恶性肿瘤中经常过度表达，并且与肿瘤细胞侵袭、转移和患者预后不良有关。最近鉴定了几种有效的、选择性的和变构的 PTP4A3 小分子抑制剂。该系列的先导化合物 JMS-053 (7-imino-2-phenylthieno[3,2 - c ]pyridine-4,6(5 H ,7 H)-二酮)，在小鼠体内具有较长的血浆半衰期（约 24 小时），表明可能与血清成分结合。我们通过等温滴定量热法证实 JMS-053 与人血清白蛋白结合。通过 X 射线晶体学在药物位点 3（也称为子域 IB）的人血清白蛋白中鉴定了单个 JMS-053 结合位点。然而，JMS-053 与人血清白蛋白的结合并未显着改变整个白蛋白结构。在血清白蛋白存在的情况下，JMS-053 作为 PTP4A3 和人 A2780 卵巢癌细胞生长的体外抑制剂的效力降低。JMS-053 与血清白蛋白的可逆结合可能有助于增加 JMS-053 的血浆半衰期，从而延长化合物向肿瘤的递送。