Inhibitors of lactic acid transporter MCT4

乳酸转运蛋白 MCT4 抑制剂

• 批准号: 8780410
• 负责人: Kenneth M Parnell
• 金额: $ 22.5万
• 依托单位: VETTORE, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8780410
• 关键词: Address; Applications Grants; Bioavailable; Biochemical; Biological Assay; Cancer cell line; Cause of Death; Cell Proliferation; Cell Respiration; Clinical; Clinical Trials; Diagnosis; Glucose; Goals; In Vitro; Inhibitory Concentration 50; Lactate Transporter; Lactic acid; Libraries; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Neoplasm Metastasis; Outcome; Oxidative Phosphorylation; Oxygen; Pharmaceutical Preparations; Phase; Play; Property; Renal Cell Carcinoma; Renal carcinoma; Respiration; Role; Testing; Therapeutic; Warburg Effect; Xenograft Model; aerobic glycolysis; angiogenesis; cancer cell; cancer therapy; design; in vitro Model; in vivo; inhibitor/antagonist; metabolomics; migration; novel; public health relevance; small molecule; tumor growth; tumor microenvironment; tumor xenograft

DESCRIPTION (provided by applicant): Most cancer cells are highly glycolytic, metabolizing glucose to lactic acid even when sufficient oxygen is available to perform oxidative metabolism, a phenomenon known as the Warburg effect. The Warburg effect has been shown to promote tumor growth, enable survival, and stimulate metastasis. In this project, we describe a strategy to directly antagonize the Warburg effect in cancer cells through the inhibition of MCT4, a lactic acid exporter that is required for the Warburg effect and is highly upregulated in many cancer indications. We have discovered a potent and selective small molecule inhibitor of MCT4. In this project, we will use this compound to validate MCT4 as a cancer target, using both in vitro and in vivo approaches. We will also develop more potent MCT4 inhibitors with the ultimate goal of evaluating MCT4 inhibition in clinical trials. 1

描述（由申请人提供）：大多数癌细胞是高度糖酵解的，即使在有足够的氧气进行氧化代谢的情况下，也会将葡萄糖代谢成乳酸，这种现象被称为Warburg效应。Warburg效应已被证明能促进肿瘤生长，使其存活，并刺激肿瘤转移。在这个项目中，我们描述了一种通过抑制MCT4直接拮抗癌细胞Warburg效应的策略，MCT4是Warburg效应所需的乳酸输出物，在许多癌症适应症中高度上调。我们已经发现了一种有效的选择性MCT4小分子抑制剂。在这个项目中，我们将使用这种化合物来验证MCT4作为癌症靶点，使用体外和体内方法。我们还将开发更有效的MCT4抑制剂，最终目标是在临床试验中评估MCT4抑制作用。1