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.

适当水平的蛋白质酪氨酸磷酸化，由蛋白质的可逆和动态作用协调酪氨酸激酶（PTK）和蛋白质酪氨酸磷酸酶（PTPS）对于细胞生长和存活至关重要。由于PTK和PTP的活性之间的平衡，异常的蛋白酪氨酸磷酸化，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的来源干预措施。这种针对性方法的治疗潜力已经得到了更多的良好确定比诊所中已经使用的两个PTK抑制剂。但是，获得了对PTK的抵抗力抑制剂限制耐用响应。因此，迫切需要新的目标和创新策略更有效的疗法。鉴于蛋白质酪氨酸磷酸化的可逆性，存在巨大在PTPs水平上调节疾病进展的潜力。为此，SRC同源性2（SH2）域由PTPN11基因编码的含有蛋白酪氨酸磷酸酶-2（SHP2）已被确定为A 阳性信号传感器，受体PTK介导的RAS激活所需的阳性信号传感器。另外，相当多证据表明SHP2是一种真正的癌蛋白。在白血病中发现激活SHP2突变，并且实体瘤。此外，鉴于SHP2在生长因子介导的途径中的强制性要求，挫败SHP2活性也可能证明对受体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的反应不佳。确实，最近的研究表明SHP2是内在的和获得对酪氨酸激酶靶向癌症药物的耐药性中的中央节点。我们假设这一点有效和选择性的小分子SHP2抑制剂可以用作新型抗癌剂。虽然PTP- 由于难以发展有效，选择性和生物利用的小分子抑制剂，我们已经确定了一种新型的命中化合物11A-1，该化合物抑制SHP2 针对大型PTP的IC50为200 nm，选择性超过5倍。而且，这种抑制剂有效阻止生长因子刺激ERK1/2，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和综合方法将现有的HIT 11A-1优化到临床前导管中以评估治疗潜力靶向SHP2进行癌症治疗。成功完成该项目将创造一个坚实的基础可以开发出新型的基于SHP2的靶向抗癌治疗。而且，成功的成功项目还将激发针对PTP家族其他成员的治疗剂的发展，最终影响人类健康。