Developing small molecule PTP4A3 inhibitors for ovarian cancer

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。高水平的 卵巢肿瘤中PTP4A3的mRNA和蛋白与疾病进展和复发密切相关 患者预后差，患者存活率低。癌细胞中PTP4A3的基因缺失降低了它们的 在体内存活、迁移和形成肿瘤的能力。相反，PTP4A3过表达会增加肿瘤 细胞在多种癌症中的迁移、侵袭和扩散，包括卵巢癌。这些加在一起， 数据表明，PTP4A3是OvCa的一个新的致癌分子靶点。目前，有不小的 PTP4A3分子抑制剂在任何类型癌症的临床开发中。我们发现了最有效的 已知的体外小分子PTP4A3抑制剂，其Ki为18 nM(JMS-053；7-亚氨基-2- Phenylthieno[3，2-c]pyridine-4，6(5H，7H)-dione).JMS-053对21的体外抑制作用不明显 其他蛋白磷酸酶和49个蛋白磷酸酶在1微米处，表明具有相当的特异性 PTP4A3。JMS-053杀死生长为3D球体的OvCa细胞，包括来自高级球体的细胞 浆液性和抗药性OvCa细胞系，EC50值低至600 NM。JMS-053治疗也 阻断OvCa细胞迁移，降低RhoA活性。JMS-053不抑制黑色素瘤细胞生长 人卵巢表面上皮细胞的浓度至少高达25微米·JMS-053(10毫克/公斤) 在抗药性OvCa小鼠异种移植模型中显示出抗癌活性。为了改善 JMS-053的药理性能，我们合成了具有优越性能的下一代类似物 PTP4A3在体外的IC50值，在计算上更像药物。KeViRx建议提供凭据 这些类似物用于确定哪种化合物(S)应进一步开发为潜在靶点 卵巢癌的治疗学。 我们提出了三项任务：任务1.确定JMS-053类似物在药物敏感中的单药作用 并在体外耐药人卵泡刺激素。任务2.确定JMS-053及其类似物与 临床批准的Ovca体外治疗药物。任务3.调查可容忍的最大值 选定的两个JMS-053类似物的体内剂量、药代动力学和初步抗肿瘤效果。 这些研究应该至少定位一种小分子PTP4A3抑制剂用于进一步的第二阶段SBIR 资助GMP级模拟研究的开发。

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.