Targeting PRL Phosphatases for Cancer Therapy

描述（由申请人提供）：蛋白酪氨酸磷酸酶（PTP）是信号转导途径的重要调节剂，可调节广泛的生理过程，如细胞增殖和分化、细胞周期进展、细胞间通讯、细胞迁移、代谢、基因转录、离子通道活性、免疫应答和细胞凋亡/存活决定。PTP活性的失调导致异常的酪氨酸磷酸化，这与包括癌症在内的几种人类疾病的病因学有关。PRL（再生肝磷酸酶）磷酸酶代表一类新的PTP，其对于控制细胞生长和侵袭是重要的。特别是，大量的证据已经积累表明，在许多肿瘤发生和转移过程的发展中，PRL 3的致癌作用。PRL 3的异位表达增强细胞生长，引起细胞转化，并促进肿瘤转移。重要的是，观察到的致癌活性需要PRL 3的磷酸酶活性。因此，PRL 3是一个非常有吸引力的癌症治疗靶点。本申请的目的是开发有效和选择性的小分子PRL 3抑制剂，并评估其用作抗癌治疗剂的潜力。涉及合成化学，高通量筛选，酶动力学，细胞生物学，诱变和结构生物学的多学科研究计划将被用于：1）设计和构建靶向PRL 3的新型组合文库，2）从文库中鉴定和表征有效的和选择性的PRL 3抑制剂，3）评估所选PRL 3抑制剂的细胞功效，（4）确定PRL 3抑制的分子基础。该项目的成功完成将为开发针对PRL 3的新型抗癌药物奠定坚实的基础。此外，从该项目中获得的有效和选择性的PRL 3抑制剂也将作为研究工具，以描述PRL 3在正常生理学和某些癌症发病机制中的功能。获得这些知识对于了解PRL 3介导的肿瘤生长和转移以及开发针对PRL 3的新型抗癌疗法至关重要。磷酸酶PRL 3与肿瘤生长和转移有关，因此代表了抗癌治疗的有吸引力的靶标。本申请的目的是开发有效和选择性的小分子PRL 3抑制剂，并评估其用作抗癌剂的潜力。

DESCRIPTION (provided by applicant): Protein tyrosine phosphatases (PTPs) are important modulators of signal transduction pathways that regulate a wide range of physiological processes such as cell proliferation and differentiation, progression through the cell cycle, cell-cell communication, cell migration, metabolism, gene transcription, ion channel activity, immune response and apoptosis/survival decisions. Deregulation of PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. The PRL (phosphatase of regenerating liver) phosphatases represent a novel class of PTPs that are important for controlling cellular growth and invasion. In particular, substantial evidence has accumulated that suggests an oncogenic role for PRL3 in the development of a number of tumorigenesis and metastasis processes. Ectopic expression of PRL3 enhances cell growth, causes cell transformation, and promotes tumor metastasis. Importantly, the phosphatase activity of PRL3 is required for the observed oncogenic activity. Consequently, PRL3 is a highly attractive target for cancer therapy. The goals of this application are to develop potent and selective small molecule PRL3 inhibitors and to evaluate their potential to be used as anti-cancer therapeutics. A multidisciplinary research program involving synthetic chemistry, high throughput screening, enzyme kinetics, cell biology, mutagenesis, and structural biology will be employed to: 1) Design and construct novel combinatorial libraries targeted to PRL3, 2) Identify and characterize potent and selective PRL3 inhibitors from the libraries, 3) Assess the cellular efficacy of the selected PRL3 inhibitors, and 4) Determine the molecular basis of PRL3 inhibition. Successful completion of this project will create a solid foundation upon which novel anti-cancer agents targeted to PRL3 can be developed. In addition, potent and selective PRL3 inhibitors acquired from this project will also serve as research tools to delineate the function of PRL3 in normal physiology and in the pathogenesis of certain cancers. Obtaining this knowledge is vital for understanding the PRL3-mediated tumor growth and metastasis, and for the development of novel anti-cancer therapies targeted to PRL3. The phosphatase PRL3 has been implicated in tumor growth and metastasis and thus represents an attractive target for anti-cancer therapy. The goals of this application are to develop potent and selective small molecule PRL3 inhibitors and to evaluate their potential to be used as anti-cancer agents.