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，PTP 4A 3，作为卵巢癌（OvCa）的靶向治疗。水平升高 卵巢肿瘤中PTP 4A 3 mRNA和蛋白与疾病进展和复发相关， 患者预后和患者存活率差。癌细胞中PTP 4A 3的遗传缺失减少了其 在体内存活、迁移和形成肿瘤的能力。相反，PTP 4A 3过表达增加了肿瘤的发生。 包括OvCa在内的多种癌症中的细胞迁移、侵袭和扩散。综上所述各项 数据表明PTP 4A 3是OvCa的新的致癌分子靶标。目前，没有小 分子PTP 4A 3抑制剂用于任何类型的癌症的临床开发。我们发现了最有效的 已知的PTP 4A 3的体外小分子抑制剂，其Ki为18 nM（JMS-053; 7-亚氨基-2- 苯基噻吩并[3，2-c]吡啶-4，6（5 H，7 H）-二酮）。JMS-053在体外对21 其他蛋白磷酸酶和49种激酶在1 µM时，表明对 PTP4A3. JMS-053杀死了生长为3D球状体的OvCa细胞，包括那些来自高级别 浆液性和耐药OvCa细胞系，EC 50值低至600 nM。JMS-053治疗还 阻断OvCa细胞的迁移并降低RhoA活性。JMS-053没有抑制细胞的生长。 人卵巢表面上皮细胞，浓度至少高达25 µM。JMS-053（10 mg/kg） 在耐药OvCa的鼠异种移植模型中显示抗癌活性。提高 我们已经合成了下一代类似物，具有上级 体外PTP 4A 3的IC 50值，计算结果更接近药物。KeViRx建议认证 这些类似物，以确定哪些化合物应进一步发展为潜在的目标， OvCa的治疗方法 我们提出三项任务：任务1。定义JMS-053类似物在药物敏感性中的单药作用 和抗人OvCa。任务2.测定JMS-053及其类似物与 临床批准的药物用于体外治疗OvCa。任务3.研究最大耐受量 两种选择的JMS-053类似物的体内剂量、药代动力学和初步抗肿瘤功效。 这些研究应定位至少一种小分子PTP 4A 3抑制剂用于进一步的II期SBIR 资助GMP级类似物研究的开发。