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Development of SHP2 inhibitors for targeted anti-cancer therapy

开发用于靶向抗癌治疗的SHP2抑制剂

基本信息

批准号：
9891029
负责人：
Zhong-Yin Zhang
金额：
$ 43.6万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891029
关键词：
Active Sites Affinity Animal Model Antineoplastic Agents Bioavailable Biochemical Biological Assay Cancer Etiology Cell Proliferation Cell Survival Clinic Colon Carcinoma Complex Crystallization Development Disease Progression Drug Kinetics Enzymes Equilibrium Etiology Event Family Foundations Glioblastoma Goals Growth Factor Health Human In Vitro Lead Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Mutation Nature Neuroblastoma Noonan Syndrome Oncogenic Oncoproteins Outcome PTPN11 gene Pathway interactions Pharmaceutical Chemistry Pharmacology Primary carcinoma of the liver cells Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Receptor Activation Receptor Protein-Tyrosine Kinases Regulation Research Resistance Resolution Risk Roentgen Rays Signal Transduction Solid Solid Neoplasm Solubility Source Structure System Technology Testing Therapeutic Therapeutic Agents Therapeutic Intervention Toxic effect Transducers Tyrosine Kinase Inhibitor Tyrosine Phosphorylation Validation anticancer activity anticancer treatment base cancer therapy cell growth design developmental disease drug development drug discovery druggable target effective therapy gain of function human disease improved in vivo inhibitor/antagonist innovation interest kinase inhibitor leukemia melanoma member molecular targeted therapies novel novel anticancer drug pre-clinical response small molecule small molecule inhibitor success therapeutic development therapeutic target tumor growth

项目摘要

Proper level of protein tyrosine phosphorylation, coordinated by the reversible and dynamic action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is essential for cell growth and survival. Aberrant protein tyrosine phosphorylation, due to perturbed balance between the activities of PTKs and PTPs, is linked to the etiology of numerous human diseases, including cancer. Consequently, signaling events driven by dysregulated protein tyrosine phosphorylation offer a rich source of molecular targets for therapeutic interventions. The therapeutic potential for such a targeted approach has been well established by the more than two-dozen PTK inhibitors that are already used in the clinic. However, acquired resistance to PTK inhibitors limit durable responses. Therefore, new targets and innovative strategies are desperately needed for more effective therapy. Given the reversible nature of protein tyrosine phosphorylation, there is enormous potential to modulate disease progression at the level of PTPs. To this end, the Src homology 2 (SH2) domain containing protein tyrosine phosphatase-2 (SHP2), encoded by the Ptpn11 gene, has been established as a positive signal transducer, required for receptor PTK-mediated Ras activation. In addition, considerable evidence indicates that SHP2 is a bona fide oncoprotein. Activating SHP2 mutations are found in leukemia and solid tumors. Moreover, given the obligatory requirement of SHP2 in growth factor-mediated pathways, thwarting SHP2 activity may also prove effective for cancers caused by abnormal activation of receptor PTKs, some of which respond poorly to kinase inhibitor monotherapy. Indeed, recent studies indicate that SHP2 is a central node in intrinsic and acquired resistance to tyrosine kinase targeted cancer drugs. We hypothesize that potent and selective small molecule SHP2 inhibitors can serve as novel anti-cancer agents. Although PTP- based drug discovery has been a challenge in the field, due to difficulty in developing potent, selective and bioavailable small molecule inhibitors, we have identified a novel hit compound 11a-1 that inhibits SHP2 with an IC50 of 200 nM and over 5-fold selectivity against a large panel of PTPs. Moreover, this inhibitor efficaciously blocks growth factor stimulated Erk1/2 and Akt activation, cell proliferation, and tumor growth in a number of in vitro and in vivo systems. The overall goal of this proposal is to employ a multifaceted and integrated approach to optimize the existing hit 11a-1 into preclinical leads to assess the therapeutic potential of targeting SHP2 for cancer treatment. Successful completion of this project will create a solid foundation upon which novel SHP2-based targeted anti-cancer therapy can be developed. Moreover, success of this project will also galvanize the development of therapeutics targeting other members of the PTP family, ultimately impacting broadly on human health.

蛋白质酪氨酸磷酸化水平适当，由蛋白质的可逆和动态作用协调酪氨酸激酶（PTK）和蛋白酪氨酸磷酸酶（PTP）对于细胞生长和存活至关重要。由于 PTK 和 PTP 活性之间的平衡受到干扰，蛋白质酪氨酸磷酸化异常，与包括癌症在内的许多人类疾病的病因有关。因此，信号事件驱动通过失调的蛋白质酪氨酸磷酸化，为治疗提供了丰富的分子靶标来源干预措施。更多的研究已经充分证实了这种靶向方法的治疗潜力超过两打已在临床使用的 PTK 抑制剂。然而，获得性PTK耐药抑制剂限制持久反应。因此，迫切需要新的目标和创新的策略。更有效的治疗。鉴于蛋白质酪氨酸磷酸化的可逆性，存在巨大的在 PTP 水平上调节疾病进展的潜力。为此，Src同源2（SH2）结构域含有由 Ptpn11 基因编码的蛋白酪氨酸磷酸酶 2 (SHP2) 已被确定为正信号转导器，是受体 PTK 介导的 Ras 激活所必需的。此外，相当大的有证据表明 SHP2 是一种真正的癌蛋白。在白血病和癌症中发现激活 SHP2 突变实体瘤。此外，考虑到 SHP2 在生长因子介导的途径中的强制性要求，阻止 SHP2 活性也可能对受体 PTK 异常激活引起的癌症有效，其中一些对激酶抑制剂单一疗法反应不佳。事实上，最近的研究表明 SHP2 是一种对酪氨酸激酶靶向癌症药物的内在和获得性耐药的中心节点。我们假设有效且选择性的小分子 SHP2 抑制剂可以作为新型抗癌药物。虽然 PTP- 基于药物的发现一直是该领域的一个挑战，因为难以开发有效的、选择性的和生物可利用的小分子抑制剂，我们发现了一种新的热门化合物 11a-1，它可以抑制 SHP2 IC50 为 200 nM，针对大量 PTP 的选择性超过 5 倍。此外，该抑制剂有效阻断生长因子刺激的 Erk1/2 和 Akt 激活、细胞增殖和肿瘤生长体外和体内系统的数量。该提案的总体目标是采用多方面的、将现有命中 11a-1 优化为临床前先导化合物的综合方法，以评估治疗潜力以 SHP2 为靶标进行癌症治疗。该项目的成功完成将为该项目奠定坚实的基础在此基础上可以开发新型基于SHP2的靶向抗癌疗法。而且，本次活动的成功项目还将促进针对 PTP 家族其他成员的疗法的开发，最终广泛影响人类健康。