Structure-based design of Hv1 proton channel blockers as potential anti-neoplasti

基于结构的 Hv1 质子通道阻滞剂设计作为潜在的抗肿瘤药物

• 批准号: 8696628
• 负责人: Mona Wood
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696628
• 关键词: Accounting; Acids; Address; Affinity; Antineoplastic Agents; Apoptosis; Arginine; Binding; Brain; Breast; Breast Cancer Cell; Cancer Diagnostics; Cancer Patient; Cancer cell line; Cause of Death; Cell Proliferation; Cell Survival; Cessation of life; Characteristics; Charge; Clinical; Clinical Trials; Collaborations; Data; Development; Diagnosis; Drug Binding Site; Drug Targeting; Electrophysiology (science); Extracellular Matrix; Extracellular Space; Free Energy; Gated Ion Channel; Goals; Homology Modeling; Human; Hydrogen Bonding; In Vitro; Invaded; Ion Channel; Ion Channel Protein; Ions; Knowledge; Lung; Malignant Neoplasms; Migration Assay; Modeling; Modification; Molecular; Molecular Conformation; Motion; Neoplasm Metastasis; Neuropathy; Outcome; Pathway interactions; Peptide Hydrolases; Pharmacologic Substance; Play; Prevention; Process; Protons; RNA Interference; Recurrence; Resolution; Resources; Role; Simulate; Staging; Structural Models; Structure; Supercomputing; Surface; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Translating; Tumor Cell Invasion; United States; Water; Work; anti-cancer therapeutic; base; cancer cell; cancer therapy; cell growth; cell motility; channel blockers; computer studies; design; extracellular; improved; in vitro Assay; in vitro activity; in vivo; insight; ion channel blocker; malignant breast neoplasm; molecular dynamics; neoplastic; neoplastic cell; novel; novel diagnostics; overexpression; pH gradient; patch clamp; public health relevance; research study; simulation; small molecule; therapeutic target; treatment strategy; tumor; tumor progression; voltage; water sampling

DESCRIPTION (provided by applicant): It is estimated that in 2011, 1.5 million people were diagnosed with some form of cancer and over 500,000 died of the disease.1 To improve clinical outcomes, new targets for cancer therapeutics are desirable. Towards this end, research studies in the past few decades have uncovered ion channel proteins as new targets for cancer therapy.6, 7 The Hv1 proton channel8,9 is one of the latest ion channels to emerge as a potential target for cancer diagnostics and treatment. The channel is preferentially expressed in highly metastatic human breast cancer cell lines and tumors, and appears to be essential for the cancer cell's ability to invade and metastasize.10 The channel likely contributes to cancer progression by helping to maintain the dysregulated pH gradient (high intracellular pH and low extracellular pH) characteristic of most cancers.11 The increased H+ secretion from Hv1 overexpression may aid cell survival by inhibiting acid-induced apoptosis. Furthermore, the subsequent acidification of the extracellular space stimulates acid-activated proteases to degrade the extracellular matrix, facilitating tumor cell invasion and dissemination.12 Functional blockade of Hv1 conductance in vivo and in vitro has been shown to significantly inhibit cancer progression and metastasis, highlighting channel blockade as a promising new avenue for cancer therapeutics.10 In previous studies,10,13 the functional blockade of Hv1 in vivo and in vito was achieved using RNA-interference technology. We propose, for the first time, to study small molecule blockers of Hv1 as antineoplastic therapeutics. To rationally design small molecules with high affinity for the channel, we develop a structural model for Hv1.5 Detailed atomistic structure/function data from molecular dynamics simulations of the model will address questions about how Hv1 is able to sense voltage and conduct protons, which will help to establish basic principles of ion conduction through voltage-sensing domains. Answers to these questions will guide the design of high affinity Hv1 blockers, which will be evaluated for their therapeutic potential to inhibit cancer progression using cell proliferation and migration assays. We hypothesize that these computational studies and in vitro assays will support Hv1 blockade as a viable mechanism for breast cancer cell inhibition and allow for the development of novel antineoplastic pharmaceuticals.

描述（由申请人提供）：据估计，在2011年，150万人被诊断患有某种形式的癌症，超过50万人死于该疾病。1为了改善临床结果，需要癌症治疗的新靶点。为此，过去几十年的研究已经发现离子通道蛋白是癌症治疗的新靶点。6，7 Hv 1质子通道8，9是最新出现的离子通道之一，是癌症诊断和治疗的潜在靶点。该通道优先在高转移性人乳腺癌细胞系和肿瘤中表达，并且似乎对于癌细胞的侵袭和转移能力是必不可少的。10该通道可能通过帮助维持失调的pH梯度而促进癌症进展（高细胞内pH值和低细胞外pH值）的特征。11增加的H+来自Hv 1过表达的分泌物可通过抑制酸诱导的细胞凋亡来帮助细胞存活。此外，细胞外空间的后续酸化刺激酸活化的蛋白酶降解细胞外基质，促进肿瘤细胞侵袭和扩散。12体内和体外Hv 1传导的功能性阻断已显示出显著抑制癌症进展和转移，突出了通道阻断作为癌症治疗的有希望的新途径。使用RNA干扰技术实现了体内和体外Hv 1的功能性阻断。我们建议，第一次，研究Hv 1的小分子阻断剂作为抗病毒治疗。为了合理地设计具有高亲和力的通道的小分子，我们开发了一个结构模型Hv1.5详细的原子结构/功能数据从分子动力学模拟的模型将解决有关Hv 1如何能够感测电压和传导质子的问题，这将有助于通过电压传感域建立离子传导的基本原理。这些问题的答案将指导高亲和力Hv 1阻断剂的设计，将使用细胞增殖和迁移试验评估其抑制癌症进展的治疗潜力。我们假设这些计算研究和体外试验将支持Hv 1阻断作为乳腺癌细胞抑制的可行机制，并允许开发新型抗肿瘤药物。