Screening for Novel CBS Inhibitors for Cancer Therapy

筛选用于癌症治疗的新型 CBS 抑制剂

• 批准号: 8707284
• 负责人: Mark R Hellmich
• 金额: $ 22.5万
• 依托单位: CBS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707284
• 关键词: Aminooxyacetic Acid; Animals; Attenuated; Bioenergetics; Biological; Biological Assay; Biological Process; Blood; Blood Vessels; Cancer Patient; Cell Proliferation; Cell Survival; Cells; Clinical; Collection; Colorectal Cancer; Colorectal Neoplasms; Communities; Cystathionine; Cysteine; Data; Dependency; Dose; Drug usage; Electron Transport; Ensure; Environment; Enzymes; Evaluation; FDA approved; Foundations; Gases; Glycolysis; Growth; HCT116 Cells; Head; Homocysteine; Homocystine; Hormones; Human; Human Biology; Hydrogen Sulfide; Hydroxylamine; In Vitro; International; Investigational Therapies; Lead; Libraries; Measurement; Measures; Mediator of activation protein; Metabolism; Methods; Methylene blue; Mitochondria; Neoplasm Metastasis; Nutrient; Patients; Pharmaceutical Preparations; Phase; Play; Process; Production; Proteins; Recombinants; Role; Small Business Technology Transfer Research; Smell Perception; Specificity; Staging; Testing; Texas; Therapeutic; Translations; Tumor Expansion; Tumor Tissue; United States National Institutes of Health; Universities; Up-Regulation; Work; base; cancer cell; cancer therapy; design; efficacy testing; extracellular; feeding; follow-up; in vivo; inhibitor/antagonist; malignant colon tumor; migration; neoplastic cell; new growth; novel; preclinical study; public health relevance; research clinical testing; research study; response; screening; small molecule libraries; sucking; tumor; tumor growth

DESCRIPTION (provided by applicant): Recent studies of the applicants support the role of the endogenous gaseous biological mediator hydrogen sulfide (H2S) in colorectal cancer: selective upregulation of cystathionine-b-synthase (CBS) and the subsequent production of H2S in colonic cancer cells serves as a pro-survival factor by stimulating tumor cell bioenergetics, growth, proliferation, migration and invasion. This work identifies CBS as a novel antitumor target. In order to advance the clinical translation of this concept, we will pursue the following two Aims: Aim #1. To conduct screening a composite library of clinical drugs, drug-like compounds and pharmacologically active molecules (>5,000 compounds) to identify novel pharmacological inhibitors of CBS, with the aim of drug repurposing for cancer therapy. In Aim #2, Inhibitors identified in the cell-based screen will subsequently enter specificity and selectivty screening, followed by bioenergetics studies and studies of tumor cell proliferation in vitro. Successful completion of the current project will be evidenced by the identification of at least one clinically used drug (already used for non-oncological indications), which exerts CBS inhibitory and anti-proliferative effects, at concentrations that are therapeutically achievable in patients. Successful identification of such compound will trigger a Phase II STTR project, aimed at in vivo PK/PD studies and preclinical IND-enabling studies, culminating in the clinical repurposing of the lead compound. The applicant team (the PI at CBS Therapeutics and the head of the subcontract at the University of Texas Galveston) has all necessary theoretical and practical expertise to conduct the proposed work.

描述（由申请人提供）：申请人的最近研究支持内源性气态生物介质硫化氢（H2S）在结肠直肠癌中的作用：结肠癌细胞中胱硫醚-b-合酶（CBS）的选择性上调和随后H2S的产生通过刺激肿瘤细胞生物能量学、生长、增殖、迁移和侵袭而充当促存活因子。这项工作确定CBS作为一种新的抗肿瘤靶点。为了推进这一概念的临床转化，我们将追求以下两个目标：目标1。筛选临床药物、类药物化合物和生物活性分子的复合库（> 5，000种化合物），以鉴定CBS的新型药理学抑制剂，目的是将药物再利用于癌症治疗。在目标#2中，在基于细胞的筛选中鉴定的抑制剂随后将进入特异性和选择性筛选，随后进行生物能量学研究和体外肿瘤细胞增殖研究。当前项目的成功完成将通过确定至少一种临床使用的药物（已用于非肿瘤适应症）来证明，该药物在治疗上可达到的浓度下发挥CBS抑制和抗增殖作用， 患者此类化合物的成功鉴定将触发II期STTR项目，旨在进行体内PK/PD研究和临床前IND使能研究，最终实现先导化合物的临床再利用。申请人团队（CBS Therapeutics的PI和德克萨斯大学加尔维斯顿的研究负责人）拥有开展拟议工作所需的所有理论和实践专业知识。