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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：
10113552
负责人：
Zhong-Yin Zhang
金额：
$ 42.9万
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113552
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 pre-clinical assessment 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）和蛋白酪氨酸磷酸酶（PTPs）对于细胞生长和存活是必需的。异常的蛋白酪氨酸磷酸化，由于PTKs和PTPs活性之间的平衡被扰乱，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点来源，干预措施。这种靶向方法的治疗潜力已经被更多的人所证实。超过二十几种已经在临床上使用的PTK抑制剂。然而，获得性耐药PTK 抑制剂限制了持久的反应。因此，迫切需要新的目标和创新战略，更有效的治疗。鉴于蛋白质酪氨酸磷酸化的可逆性，在PTP水平调节疾病进展的潜力。为此，Src同源2（SH 2）结构域含有蛋白酪氨酸磷酸酶-2（SHP 2），由Ptpn 11基因编码，已被确定为一种阳性信号转导子，受体PTK介导的Ras激活所需。此外，相当多的有证据表明SHP 2是一种真正的癌蛋白。在白血病中发现了激活SHP 2突变，实体瘤此外，考虑到生长因子介导的途径中对SHP 2的强制性要求，阻碍SHP 2活性也可以证明对由受体PTK的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差。事实上，最近的研究表明，SHP 2是一种酪氨酸激酶靶向抗癌药物的内在和获得性耐药性的中心节点。我们假设有效的和选择性的小分子SHP 2抑制剂可用作新的抗癌剂。虽然PTP- 由于难以开发有效的、选择性的和有效的药物，生物可利用的小分子抑制剂，我们已经确定了一种新的命中化合物11 a-1，抑制SHP 2， IC 50为200 nM，对大量PTP的选择性超过5倍。此外，这种抑制剂有效地阻断生长因子刺激的Erk 1/2和Akt活化、细胞增殖和肿瘤生长，体外和体内系统的数量。这项建议的总体目标是采用一种多方面和将现有的hit 11 a-1优化为临床前线索的综合方法，以评估治疗潜力靶向SHP 2用于癌症治疗。这个项目的成功完成将为基于此可以开发新的基于SHP 2的靶向抗癌疗法。此外，这一成功该项目还将促进针对PTP家族其他成员的治疗方法的开发，最终对人类健康产生广泛影响。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin regulates POMC neuronal plasticity to control glucose metabolism.

DOI：
10.7554/elife.38704
发表时间：
2018-09-19
期刊：
eLife
影响因子：
7.7
作者：
Dodd GT;Michael NJ;Lee-Young RS;Mangiafico SP;Pryor JT;Munder AC;Simonds SE;Brüning JC;Zhang ZY;Cowley MA;Andrikopoulos S;Horvath TL;Spanswick D;Tiganis T
通讯作者：
Tiganis T

Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B.

DOI：
10.1021/acs.jmedchem.0c00302
发表时间：
2020-09-10
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Ruddraraju KV;Aggarwal D;Niu C;Baker EA;Zhang RY;Wu L;Zhang ZY
通讯作者：
Zhang ZY

Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation.

疾病相关 SHP2 突变体的相分离是 MAPK 过度激活的基础。

DOI：
10.1016/j.cell.2020.09.002
发表时间：
2020-10-15
期刊：
Cell
影响因子：
64.5
作者：
Zhu G;Xie J;Kong W;Xie J;Li Y;Du L;Zheng Q;Sun L;Guan M;Li H;Zhu T;He H;Liu Z;Xia X;Kan C;Tao Y;Shen HC;Li D;Wang S;Yu Y;Yu ZH;Zhang ZY;Liu C;Zhu J
通讯作者：
Zhu J

Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems.