Small Molecule Inhibitors for the Oncogenic Protein Tyrosine Phosphatase SHP2

致癌蛋白酪氨酸磷酸酶 SHP2 的小分子抑制剂

基本信息

批准号：
8067184
负责人：
Zhong-Yin Zhang
金额：
$ 31万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8067184
关键词：
Action Potentials Active Sites Adhesions Affinity Apoptosis Binding Proteins Biological Biological Availability Cell Membrane Permeability Cell membrane Cell physiology Cellular biology Charge Chemicals Chemistry Complex Cytokine Receptors Disease Enzyme Kinetics Epidermal Growth Factor Receptor Equilibrium Etiology Event Excision Exhibits Foundations Goals Growth Growth Factor Receptor Genes Hematologic Neoplasms Individual Indoles Integrins Interdisciplinary Study Investigation Libraries Link MAPK3 gene Malignant Neoplasms Molecular Mutation Nature Noonan Syndrome Oncogenes Oncogenic PTPN11 gene Phosphoric Monoester Hydrolases Phosphotyrosine Physiology Property Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Receptor Protein-Tyrosine Kinases Regulation Research Salicylic Acids Signal Transduction Site-Directed Mutagenesis Solid Solid Neoplasm Src homology 2 domain-containing, transforming protein 1 Structure Synthesis Chemistry Techniques Therapeutic Transducers Treatment Efficacy Tyrosine Tyrosine Phosphorylation X-Ray Crystallography base cell motility cell transformation combinatorial chemistry drug discovery gain of function high throughput screening human disease inhibitor/antagonist leukemia mimetics novel pharmacophore phosphatase inhibitor preference programs public health relevance small molecule src-Family Kinases therapeutic development therapeutic target three dimensional structure tool

Action Potentials Active Sites Adhesions Affinity Apoptosis Binding Proteins Biological Biological Availability Cell Membrane Permeability Cell membrane Cell physiology Cellular biology Charge Chemicals Chemistry Complex Cytokine Receptors Disease Enzyme Kinetics Epidermal Growth Factor Receptor Equilibrium Etiology Event Excision Exhibits Foundations Goals Growth Growth Factor Receptor Genes Hematologic Neoplasms Individual Indoles Integrins Interdisciplinary Study Investigation Libraries Link MAPK3 gene Malignant Neoplasms Molecular Mutation Nature Noonan Syndrome Oncogenes Oncogenic PTPN11 gene Phosphoric Monoester Hydrolases Phosphotyrosine Physiology Property Protein Dephosphorylation Protein Tyrosine Kinase Protein Tyrosine Phosphatase Receptor Protein-Tyrosine Kinases Regulation Research Salicylic Acids Signal Transduction Site-Directed Mutagenesis Solid Solid Neoplasm Src homology 2 domain-containing, transforming protein 1 Structure Synthesis Chemistry Techniques Therapeutic Transducers Treatment Efficacy Tyrosine Tyrosine Phosphorylation X-Ray Crystallography base cell motility cell transformation combinatorial chemistry drug discovery gain of function high throughput screening human disease inhibitor/antagonist leukemia mimetics novel pharmacophore phosphatase inhibitor preference programs public health relevance small molecule src-Family Kinases therapeutic development therapeutic target three dimensional structure tool

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项目摘要

DESCRIPTION (provided by applicant): Reversible tyrosine phosphorylation, regulated by the coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is of critical importance to signaling events that underlie virtually all essential cellular processes. Not surprisingly, disturbance of the balance between PTK and PTP activity leads to aberrant tyrosine phosphorylation, causing many human diseases, including cancer. The long-term objective of the proposed research program is to develop small molecule therapeutics targeting SHP2 (Src homology 2 domain-containing phosphatase 2), which is the first bona fide oncogene identified in the PTP superfamily. SHP2 is required for Ras/ERK1/2 activation downstream of most receptor tyrosine kinases, cytokine receptors, and integrins. In addition, gain-of-function SHP2 mutations are known to cause the autosomal dominant disorder Noonan Syndrome, multiple forms of leukemia and solid tumors. Consequently, SHP2 represents an attractive anti-cancer and anti-leukemia target. Unfortunately, PTPs are exceptionally challenging targets for drug discovery, due primarily to the highly positively charged nature of the PTP active site. Indeed, almost all existing PTP inhibitors contain negatively charged nonhydrolyzable phosphotyrosine mimetics, and suffer poor membrane permeability and cellular efficacy. In order to overcome the bioavailability issue, we have developed a breakthrough chemistry platform based on bicyclic salicylic acid pharmacophores that are sufficiently polar to bind the PTP active site, yet remain capable of efficiently crossing cell membranes. We have acquired an indole salicylic acid based SHP2 inhibitor II-B08, with a low 5M affinity for SHP2 and several fold preference for SHP2 over a panel of mammalian PTPs. Moreover, II-B08 exhibits outstanding cellular activity. However, the potency and selectivity displayed by II-B08 are relatively modest, and are inadequate for chemical biological investigation and therapeutic development. To move forward, we have obtained a three-dimensional structure of SHP2 in complex with II-B08, which reveals molecular determinants that can be exploited for the acquisition of SHP2 inhibitors with enhanced properties. In this proposal, we will apply a structure-guided focused library synthesis strategy to optimize II-B08 into highly potent and selective SHP2 inhibitors. We will also evaluate the cellular efficacy, therapeutic potential, as well as mechanism of action of the SHP2 inhibitory agents. The multidisciplinary research program utilizes techniques in synthetic and combinatorial chemistry, high-throughput screening, enzyme kinetics, cell biology, signal transduction, site-directed mutagenesis, and X-ray crystallography. Successful completion of this project will create a solid foundation upon which novel agents targeted to SHP2 can be developed for individuals with hematologic malignancies and cancer. In addition, potent and selective SHP2 inhibitors will also serve as powerful research tools to delineate the function of SHP2 in normal physiology and to elucidate the events underlying SHP2-evoked transformation. PUBLIC HEALTH RELEVANCE: The SHP2 protein tyrosine phosphatase is an oncogene responsible for the autosomal dominant disorder Noonan Syndrome, multiple forms of leukemia and solid tumors and thus represents an attractive target for anti-cancer and anti-leukemia therapy. The goals of this application are to develop potent and selective small molecule SHP2 inhibitors and to evaluate their potential to be used as anti-hematologic malignancies and cancer agents.

描述（由申请人提供）：可逆酪氨酸磷酸化，受蛋白酪氨酸激酶（PTKS）和蛋白质酪氨酸磷酸酶（PTP）的协调作用调节，对于几乎所有必需细胞过程的基础的信号事件至关重要。毫不奇怪，PTK和PTP活性之间平衡的干扰会导致异常的酪氨酸磷酸化，从而导致许多人类疾病，包括癌症。拟议的研究计划的长期目标是开发针对SHP2的小分子疗法（SRC同源性2含域的磷酸酶2），这是PTP超级家族中第一个真正的癌基因。大多数受体酪氨酸激酶，细胞因子受体和整联蛋白的RAS/ERK1/2激活所需的SHP2是必需的。此外，已知功能获得的SHP2突变会导致常染色体显性疾病Noonan综合征，多种形式的白血病和实体瘤。因此，SHP2代表了一个有吸引力的抗癌和抗白血病靶标。不幸的是，PTP是药物发现的极具挑战性的目标，这主要是由于PTP活性部位的高度带电性质。实际上，几乎所有现有的PTP抑制剂都包含带负电荷的非溶解磷酸酪氨酸模拟物，并且膜渗透性和细胞功效差。为了克服生物利用度问题，我们建立了一个基于双环水杨酸药理的突破性化学平台，这些平台足够极了以结合PTP活性位点，但仍能有效地越过细胞膜。我们已经获得了基于吲哚水杨酸的SHP2抑制剂II-B08，对SHP2的亲和力较低，而SHP2在一组哺乳动物的PTP上的偏好是SHP2的几倍偏爱。此外，II-B08表现出出色的细胞活性。但是，II-B08所表现出的效力和选择性相对适度，并且不足以进行化学生物学研究和治疗性发育。为了向前发展，我们获得了与II-B08复合物中SHP2的三维结构，该结构揭示了可以利用这些分子决定因素，这些决定因素可以利用，以获取具有增强特性的SHP2抑制剂。在此提案中，我们将采用结构引导的集中库合成策略，以将II-B08优化为高效和选择性的SHP2抑制剂。我们还将评估SHP2抑制剂的细胞功效，治疗潜力以及作用机理。多学科研究计划在合成和组合化学，高通量筛选，酶动力学，细胞生物学，信号转导，定点诱变和X射线晶体学方面利用技术。该项目的成功完成将创造一个坚实的基础，可以为具有血液系统恶性肿瘤和癌症患者开发针对SHP2的新型代理。此外，有效和选择性的SHP2抑制剂还将用作有力的研究工具，以描绘SHP2在正常生理学中的功能并阐明SHP2引起的转化的事件。公共卫生相关性：SHP2蛋白酪氨酸磷酸酶是负责常染色体显性疾病Noonan综合征，多种形式白血病和实体瘤的癌基因，因此代表了抗癌和抗白血病治疗的有吸引力的靶标。该应用的目标是开发有效和选择性的小分子SHP2抑制剂，并评估其用作抗血液恶性肿瘤和癌症药物的潜力。