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：
9101727
负责人：
Lutz Tautz
金额：
$ 25.45万
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 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9101727
关键词：
Ablation Active Sites Allosteric Site Antineoplastic Agents 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 Disease Drug Kinetics Drug Targeting Drug resistance Enzymes Epidermal Growth Factor Receptor Exhibits Future Genetic Growth Human Knowledge Lead Maintenance Malignant Neoplasms Medical Metastatic Neoplasm to the Lung Molecular NMR Spectroscopy Nature Oncogenes Oncogenic PTPN11 gene Pathway interactions Patients Pharmaceutical Preparations Phosphotyrosine Play Property Protein Tyrosine Phosphatase Reporting Signal Pathway Signal Transduction Solubility Structure Testing Therapeutic Toxic effect Traction Tumor Burden Work X-Ray Crystallography base carcinogenesis cost cytokine drug discovery drug metabolism 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 research study 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）：乳腺癌是一种异质性疾病，其死亡率与治疗失败相关，这主要是由于大多数疗法的非特异性。事实上，除了抗人表皮生长因子受体 2 (HER2) 药物以外，大多数乳腺癌疗法都是通过全身毒性发挥作用。三阴性乳腺癌具有高侵袭性和不良预后，无法表达 HER2，治疗选择更少。因此，寻找乳腺癌新的治疗干预点是一个至关重要的未满足的医疗需求。酪氨酸磷酸酶 SHP2 由众所周知的癌基因 PTPN11 编码，是靶向癌症治疗的候选者。大量现有数据表明，SHP2 的异常催化功能是其致癌作用的原因。最近的遗传证据表明，SHP2 确实是 HER2 阳性和三阴性乳腺癌的一个新的潜在靶点，因为它的消融可以减少肿瘤负荷并减少转移进展。为了进一步研究这些现象，此类研究需要高效、特异性和有效的 SHP2 抑制剂，其特性使其适合体内实验。然而，所报道的 SHP2 抑制剂均未完全满足这些要求。开发此类化合物的主要障碍之一是与其他酪氨酸磷酸酶相比，SHP2 缺乏化合物选择性。另一个相当大的障碍是现有的 SHP2 抑制剂携带带电荷的磷酸酪氨酸模拟基团，阻碍了体内充分的化合物暴露。我们已经生成了对 SHP2 具有优异选择性的新型变构抑制剂。我们的化合物不具有这样的带电部分，因为它们不针对 SHP2 中的磷酸酪氨酸结合位点。在这里，我们建议定义这些化合物抑制 SHP2 的基础，以促进现有先导结构的化学优化以及未来的药物发现工作。具有进一步提高的效力/功效以及合适的药物代谢和药代动力学 (DMPK) 特性的优化先导化合物将被用来充分验证 SHP2 作为乳腺癌治疗的药物靶点。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，优化这些药物作为有效的药物样分子，并最终证明它们作为乳腺癌体内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 光谱来识别我们的先导化合物所针对的新型变构位点（目标 1）。我们将对 SHP2 抑制剂进行化学优化，以提高溶解度、功效和 DMPK 特性，使其适合体内研究（目标 2）。最后，我们将测试优化的 SHP2 抑制剂抑制 a) 乳腺癌细胞中的 SHP2 依赖性信号传导，b) 乳腺癌细胞的侵袭和增殖的潜力。三维培养和体内，c) 三阴性乳腺癌小鼠模型中肿瘤的维持、生长和肺转移进展（目标 3）。