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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(PTKs)和蛋白酪氨酸磷酸酶(PTPs)是细胞生长和存活所必需的。蛋白酪氨酸磷酸化异常，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学有关。因此，信令事件驱动蛋白酪氨酸磷酸化异常为治疗提供了丰富的分子靶点干预措施。这种靶向治疗的潜力已经被更多的人很好地确立了比已经在临床上使用的24种PTK抑制剂更多。然而，对PTK的获得性抵抗抑制剂限制了持久的反应。因此，迫切需要新的目标和创新的战略更有效的治疗方法。鉴于蛋白质酪氨酸磷酸化的可逆性，有巨大的在PTP水平上调节疾病进展的可能性。为此，Src同源2(SH2)结构域由Ptpn11基因编码的含蛋白酪氨酸磷酸酶-2(SHP2)已被确定为一种受体PTK介导的RAS激活所需的正信号转导。此外，相当大的有证据表明SHP2是一种真正的癌蛋白。激活SHP2突变在白血病和实体瘤。此外，鉴于SHP2在生长因子介导的途径中的强制性要求，抑制SHP2活性也可能被证明对由受体PTKs异常激活引起的癌症有效，其中一些对激酶抑制剂单一治疗的反应很差。事实上，最近的研究表明SHP2是一种中枢结节内固有和获得性耐药酪氨酸激酶靶向抗癌药物。我们假设高效、选择性的小分子SHP2抑制剂可作为新型抗癌药物。虽然PTP- 基于药物的发现一直是该领域的一个挑战，因为开发有效的、选择性的和生物可用小分子抑制剂，我们已经确定了一种新的HIT化合物11a-1，它通过 IC50为200纳米，对大量PTP的选择性超过5倍。此外，这种抑制物有效阻断生长因子刺激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。这项提案的总体目标是采用多方面的和将现有的HIT 11a-1优化为临床前导联以评估治疗潜力的综合方法将SHP2作为治疗癌症的靶点。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，可以开发基于SHP2的新型靶向抗癌治疗。而且，这件事的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.