Developing small molecule PTP4A3 inhibitors for ovarian cancer

开发卵巢癌小分子 PTP4A3 抑制剂

• 批准号: 9769367
• 负责人: JOHN S. LAZO
• 金额: $ 28.93万
• 依托单位: KEVIRX INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769367
• 关键词: 3-Dimensional; Cancer cell line; Clinical; Data; Development; Disease Progression; Dose; Drug Kinetics; Drug resistance; Drug-sensitive; Epithelial Cells; Funding; Genetic; Growth; Human; In Vitro; Malignant Neoplasms; Malignant neoplasm of ovary; Messenger RNA; Molecular Target; Mus; Oncogenic; Ovarian; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Phosphotransferases; Positioning Attribute; Property; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Recurrence; Research; Resistance; Serous; Small Business Innovation Research Grant; Specificity; Surface; Tumor Cell Migration; Xenograft Model; analog; anticancer activity; cancer cell; cancer type; clinical development; improved; in vivo; inhibitor/antagonist; innovation; migration; next generation; novel; outcome forecast; ovarian neoplasm; overexpression; pyridine; small molecule; small molecule inhibitor; targeted treatment; treatment strategy; tumor

Project Summary. Our objective is to develop small molecule inhibitors of the highly oncogenic protein tyrosine phosphatase, PTP4A3, as a targeted therapy for ovarian cancer (OvCa). Elevated levels of PTP4A3 mRNA and protein in ovarian tumors correlate with disease progression and recurrence, poor patient prognosis and poor patient survival. Genetic depletion of PTP4A3 in cancer cells diminishes their ability to survive, migrate and form tumors in vivo. Conversely, PTP4A3 overexpression increases tumor cell migration, invasion and dissemination in multiple cancers, including OvCa. Taken together, these data suggest PTP4A3 is a novel oncogenic molecular target for OvCa. Currently, there are no small molecule PTP4A3 inhibitors in clinical development for any type of cancer. We discovered the most potent known in vitro small molecule inhibitor of PTP4A3, which has a Ki of 18 nM (JMS-053; 7-imino-2- phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione). JMS-053 displayed no significant in vitro inhibition of 21 other protein phosphatases and 49 kinases at 1 µM, suggesting considerable specificity towards PTP4A3. JMS-053 killed OvCa cells grown as 3D spheroids, including those derived from high grade serous and drug resistant OvCa cell lines, with EC50 values as low as 600 nM. JMS-053 treatment also block the migration of OvCa cells and decreased RhoA activity. JMS-053 did not inhibit the growth of the human ovarian surface epithelial cells at concentrations at least up to 25 µM. JMS-053 (10 mg/kg) displayed anticancer activity in a murine xenograft model of drug resistant OvCa. To improve the pharmaceutical properties of JMS-053, we have synthesized next generation analogs that have superior IC50 values for PTP4A3 in vitro and are computationally more drug-like. KeViRx proposes to credential these analogs to identify which compound(s) should be developed further as potential targeted therapeutics for OvCa. We propose three Tasks: Task 1. Define the single agent actions of JMS-053 analogs in drug-sensitive and -resistant human OvCa in vitro. Task 2. Determine the interactions of JMS-053 and its analogs with clinically approved drugs for the treatment of OvCa in vitro. Task 3. Investigate the maximum tolerated in vivo dose, the pharmacokinetics and preliminary antitumor efficacy of two selected JMS-053 analogs. These studies should position at least one small molecule PTP4A3 inhibitor for further Phase II SBIR funded development in GMP-grade analog studies.

项目摘要。我们的目标是开发高致癌蛋白的小分子抑制剂 酪氨酸磷酸酶，PTP4A3，作为卵巢癌（OvCa）的靶向治疗。水平升高 卵巢肿瘤中 PTP4A3 mRNA 和蛋白与疾病进展和复发相关，但较差 患者预后和患者生存率较差。癌细胞中 PTP4A3 的基因缺失会降低其活性 体内存活、迁移和形成肿瘤的能力。相反，PTP4A3 过度表达会增加肿瘤 多种癌症（包括 OvCa）中的细胞迁移、侵袭和传播。综合起来，这些 数据表明 PTP4A3 是 OvCa 的新型致癌分子靶标。目前，还没有小 分子 PTP4A3 抑制剂正在针对任何类型的癌症进行临床开发。我们发现了最有效的 已知的 PTP4A3 体外小分子抑制剂，Ki 为 18 nM（JMS-053；7-imino-2- 苯基噻吩并[3,2-c]吡啶-4,6(5H,7H)-二酮）。 JMS-053 对 21 没有显着的体外抑制作用 其他蛋白磷酸酶和 49 种激酶（1 µM），表明对 PTP4A3。 JMS-053 杀死了生长为 3D 球体的 OvCa 细胞，包括来自高等级细胞的 OvCa 细胞 浆液性和耐药性 OvCa 细胞系，EC50 值低至 600 nM。 JMS-053治疗也 阻断 OvCa 细胞的迁移并降低 RhoA 活性。 JMS-053不抑制生长 人卵巢表面上皮细胞浓度至少高达 25 µM。 JMS-053（10毫克/千克） 在耐药 OvCa 小鼠异种移植模型中显示出抗癌活性。为了改善 根据 JMS-053 的药物特性，我们合成了具有优越性能的下一代类似物 PTP4A3 的体外 IC50 值在计算上更接近药物。 KeViRx 提出凭证 这些类似物可以确定哪些化合物应该进一步开发作为潜在的靶点 OvCa 的治疗。 我们提出了三个任务： 任务 1. 定义 JMS-053 类似物在药物敏感中的单药作用 和体外耐药的人 OvCa。任务 2. 确定 JMS-053 及其类似物与 临床批准用于体外治疗 OvCa 的药物。任务 3. 调查最大容忍度 两种选定的 JMS-053 类似物的体内剂量、药代动力学和初步抗肿瘤功效。 这些研究应该为进一步的 II 期 SBIR 定位至少一种小分子 PTP4A3 抑制剂 资助 GMP​​ 级模拟研究的开发。