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

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）：可逆酪氨酸磷酸化由蛋白酪氨酸激酶（PTK）和蛋白酪氨酸磷酸酶（PTP）的协调作用调节，对于几乎所有基本细胞过程的信号转导事件至关重要。毫不奇怪，PTK 和 PTP 活性之间的平衡紊乱会导致酪氨酸磷酸化异常，从而导致许多人类疾病，包括癌症。拟议研究计划的长期目标是开发针对 SHP2（包含 Src 同源 2 结构域的磷酸酶 2）的小分子疗法，SHP2 是 PTP 超家族中发现的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下游的 Ras/ERK1/2 激活需要 SHP2。此外，已知功能获得性 SHP2 突变会导致常染色体显性遗传疾病努南综合征、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点。不幸的是，PTP 是药物发现中极具挑战性的靶标，这主要是由于 PTP 活性位点带高正电荷的性质。事实上，几乎所有现有的 PTP 抑制剂都含有带负电荷的不可水解的磷酸酪氨酸模拟物，并且膜通透性和细胞功效较差。为了克服生物利用度问题，我们开发了一种基于双环水杨酸药效团的突破性化学平台，其极性足以结合 PTP 活性位点，但仍然能够有效穿过细胞膜。我们获得了一种基于吲哚水杨酸的 SHP2 抑制剂 II-B08，它对 SHP2 的亲和力低至 5M，并且对 SHP2 的偏好程度是一组哺乳动物 PTP 的几倍。此外，II-B08 表现出出色的细胞活性。然而，II-B08 显示的效力和选择性相对较小，不足以用于化学生物学研究和治疗开发。为了进一步推进，我们获得了 SHP2 与 II-B08 复合物的三维结构，该结构揭示了可用于获得具有增强特性的 SHP2 抑制剂的分子决定因素。在本提案中，我们将应用结构引导的重点文库合成策略，将 II-B08 优化为高效、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制。该多学科研究项目利用合成和组合化学、高通量筛选、酶动力学、细胞生物学、信号转导、定点诱变和 X 射线晶体学等技术。该项目的成功完成将为针对血液系统恶性肿瘤和癌症患者开发针对 SHP2 的新型药物奠定坚实的基础。此外，有效且选择性的 SHP2 抑制剂也将作为强大的研究工具来描述 SHP2 在正常生理学中的功能，并阐明 SHP2 诱发转化的潜在事件。公共健康相关性：SHP2 蛋白酪氨酸磷酸酶是一种致癌基因，导致常染色体显性遗传疾病努南综合征、多种形式的白血病和实体瘤，因此是抗癌和抗白血病治疗的一个有吸引力的靶点。本申请的目标是开发有效且选择性的小分子 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。