Allosteric inhibition of the SHP2 oncoprotein in breast cancer

乳腺癌中 SHP2 癌蛋白的变构抑制

基本信息

批准号：
9251251
负责人：
Lutz Tautz
金额：
$ 21.21万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251251
关键词：
Ablation Active Sites Allosteric Site Binding Sites Biological Assay Biological Availability Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer therapy Cell model Cells Charge Chemicals Data Development Dimensions Disease Drug Kinetics Drug Targeting Enzymes Epidermal Growth Factor Receptor Exhibits Future Genetic Growth Growth Factor Human Knowledge Lead Maintenance Malignant Neoplasms Medical Metastatic Neoplasm to the Lung Molecular NMR Spectroscopy Nature Oncogenes Oncogenic Oncoproteins PTPN11 gene Pathway interactions Patients Pharmaceutical Preparations Phosphotyrosine Play Property Protein Inhibition Protein Tyrosine Phosphatase Reporting Resistance development Signal Pathway Signal Transduction Solubility Structure Testing Therapeutic Toxic effect Traction Tumor Burden Tumor Initiators Work X-Ray Crystallography base carcinogenesis cost cytokine drug development drug discovery drug metabolism experimental study genetic signature improved in vivo in vivo Model inhibitor/antagonist insight leukemia malignant breast neoplasm mortality mouse model novel novel strategies novel therapeutic intervention outcome forecast preclinical study public health relevance response small molecule inhibitor success targeted cancer therapy targeted treatment treatment strategy triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Breast cancers are heterogeneous diseases with significant mortality associated with failed treatment, and this is primarily due to the non-specifc nature of most therapies. Indeed, with the notable exception of anti-human epidermal growth factor receptor 2 (HER2) agents, most breast cancer therapies act through generalized toxicity. Triple-negative breast cancers, which are associated with high aggressiveness and poor prognosis, fail to express HER2 and have even less treatment options. Thus, the search for new therapeutic intervention points in breast cancers is a crucial unmet medical need. The tyrosine phosphatase SHP2, encoded by the well-known oncogene PTPN11, is a candidate for targeted cancer therapy. A plethora of existing data demonstrates that aberrant catalytic function of SHP2 is responsible for its oncogenic effects. Recent genetic evidence indicates that SHP2 is indeed a novel potential target in HER2-positive and triple negative breast cancers, as its ablation results in decreased tumor burden and reduced metastatic progression. To further investigate these phenomena, such studies require highly potent, specific, and efficacious SHP2 inhibitors with properties that make them suitable for in vivo experiments. However, none of the reported SHP2 inhibitors fully satisfies these requirements. One of the major obstacles in developing such compounds is the lack of compound selectivity for SHP2 over other tyrosine phosphatases. Another considerable hurdle is presented by the fact that existing SHP2 inhibitors carry a charged phosphotyrosine-mimicking group that precludes sufficient compound exposure in vivo. We have generated novel allosteric inhibitors with excellent selectivity for SHP2. Our compounds do not have such a charged moiety as they do not target the phosphotyrosine binding site in SHP2. Here, we propose to define the basis of SHP2 inhibition by these compounds in order to facilitate chemical optimization of existing lead structures, as well as future drug discovery efforts. Optimized leads with further increased potency/ efficacy and suitable drug metabolism and pharmacokinetics (DMPK) properties will be utilized to fully validate SHP2 as drug target for breast cancer therapy. The overarching objectives of this proposal therefore are to demonstrate the efficacy of our SHP2 inhibitors in cellular breast cancer models, to optimize the agents as potent drug like molecules, and finally to demonstrate their potential as lead agents in in vivo models of breast cancers. To achieve these objectives, we will use X-Ray crystallography and NMR spectroscopy to identify the novel allosteric site(s) targeted by our lead compounds (Aim 1). We will chemically optimize the SHP2 inhibitors for improved solubility, efficacy, and DMPK properties to make them suitable for in vivo studies (Aim 2). Finally, we will test optimized SHP2 inhibitors for their potential to inhibit a) SHP2-dependent signaling in breast cancer cells, b) invasion and proliferation of breast cancer cells in three-dimensional culture and in vivo, and c) tumor maintenance, growth, and progression to lung metastases in triple negative breast cancer mouse models (Aim 3).

描述（由申请人提供）：乳腺癌是与治疗失败有关的显着死亡率的异质疾病，这主要是由于大多数疗法的非特定性质。确实，除了明显的抗人表皮生长因子受体2（HER2）药物外，大多数乳腺癌疗法通过普遍的毒性作用。与高侵略性和预后不良有关的三阴性乳腺癌未能表达HER2，并且治疗选择更少。因此，在乳腺癌中寻找新的治疗干预点是至关重要的未满足医疗需求。由众所周知的癌基PTPN11编码的酪氨酸磷酸酶SHP2是靶向癌症治疗的候选者。许多现有数据表明，SHP2的异常催化功能负责其致癌作用。最近的遗传证据表明，SHP2确实是HER2阳性和三重阴性乳腺癌的新型潜在靶标，因为其消融导致肿瘤负担减轻并减少转移性进展。为了进一步研究这些现象，此类研究需要具有高度有效，特异性和有效的SHP2抑制剂，其特性使其适合于体内实验。但是，没有报告的SHP2抑制剂完全满足这些要求。开发这种化合物的主要障碍之一是SHP2与其他酪氨酸磷酸酶缺乏复合选择性。现有的SHP2抑制剂携带一个带电的磷酸酪氨酸模拟组的事实提出了另一个巨大的障碍，该基团排除了体内足够的复合暴露。我们已经产生了新型的变构抑制剂，对SHP2具有极好的选择性。我们的化合物没有带电的部分，因为它们不瞄准SHP2中的磷酸酪氨酸结合位点。在这里，我们建议通过这些化合物来定义SHP2抑制的基础，以促进现有铅结构的化学优化以及未来的药物发现工作。优化的铅具有进一步提高的效力/功效，合适的药物代谢和药代动力学（DMPK）特性将被用来充分验证SHP2作为乳腺癌治疗的药物靶标。因此，该提案的总体目标是证明我们的SHP2抑制剂在细胞乳腺癌模型中的功效，以优化药物为有效的药物（如分子），并最终证明其作为乳腺癌体内乳腺模型中的主要药物的潜力。为了实现这些目标，我们将使用X射线晶体学和NMR光谱法来识别我们铅化合物靶向的新型变构位（AIM 1）。我们将化学优化SHP2抑制剂，以提高溶解度，功效和DMPK特性，以使其适合于体内研究（AIM 2）。最后，我们将测试优化的SHP2抑制剂，以抑制a）乳腺癌细胞中SHP2依赖性信号传导的潜力，b）乳腺癌细胞在三维培养和体内以及c）在三阴性乳腺癌小鼠模型中维持肿瘤维持，生长和向肺转移的发展（AIM 3）。