Drug Discovery for Fatty Acid Synthase in Oncology

肿瘤学中脂肪酸合成酶的药物发现

• 批准号: 8230593
• 负责人: Jeffrey W Smith
• 金额: $ 50.36万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230593
• 关键词: Address; Adult; Affinity; Anabolism; Antineoplastic Agents; Apoptosis; Bacteria; Binding; Biological Assay; Biological Factors; Body Weight decreased; Carnitine; Cell Proliferation; Cerulenin; Chemicals; Development; Diagnosis; Dietary Carbohydrates; Disease; Dose; Drug Delivery Systems; Ensure; Enzymes; Epigallocatechin Gallate; Exhibits; Fatty acid glycerol esters; Fatty-acid synthase; Health; Holoenzymes; Human; In Vitro; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medical; Mus; Mycobacterium tuberculosis; Mycolic Acid; Pharmaceutical Preparations; Property; Recombinants; Regimen; Screening procedure; Siderophores; Small Interfering RNA; Solid Neoplasm; Therapeutic Index; Toxic effect; Transferase; Translating; Work; Xenograft Model; angiogenesis; base; cancer cell; cytotoxic; design; drug development; drug discovery; gallocatechol; in vitro Assay; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; mouse model; neoplastic cell; novel; oncology; outcome forecast; pre-clinical; prevent; public health relevance; scaffold; small molecule; tumor; tumor growth

DESCRIPTION (provided by applicant): It is projected that 500,000 people will die from cancer, and that another 1,500,000 will be diagnosed with the disease in 2008. Consequently there is a huge unmet medical need for new anti-cancer drugs. This study will focus on developing drugs against fatty acid synthase (FAS), the sole enzyme in humans that converts dietary carbohydrate to fat. FAS has only marginal importance in adults, but its activity is essential for the proliferation and survival of most tumor cells. FAS is up-regulated in all the major solid tumors, and in most cases its expression is indicative of poor prognosis. There is an overwhelming body of evidence underscoring the functional significance of FAS to tumor growth and survival, and evidence that its pharmacological inhibition can prevent tumor growth in vivo. However, no study has addressed the most important issue relevant to translating this information into the improvement of human health: can a drug-like small molecule inhibitor of FAS be developed that can be advanced into pre-clinical development? The long-term objective of this study is to address this major issue through the following Specific Aims: 1) Design and synthesize potent, selective and reversible small molecule inhibitors of the thioesterase domain of FAS. These inhibitors will be based on hits obtained from screening libraries of drug-like compounds, and on structural insights into the enzyme. 2) Evaluate the potency and selectivity of compounds synthesized in Aim 1; the FAS inhibitors will be assessed for (a) potency in assays measuring the catalytic activity of the recombinant thioesterase and the purified FAS holoenzyme, (b) for off-target effects against other human thioesterases, (c) cytotoxic potency against lipogenic and non-lipogenic tumor cells, (d) physicochemical and ADME/T properties using standard in vitro assays. 3) Evaluate the novel inhibitors of FAS for anti-tumor activity. The compounds will be evaluated for the ability to reduce tumor growth in mouse xenograft models of human breast and prostate cancer. The intent of this project is to deliver a drug-like compound with nanomolar affinity for FAS that exhibits anti- tumor activity in vivo, with a reasonable therapeutic index. PUBLIC HEALTH RELEVANCE: This study focuses on developing anti-cancer drugs against fatty acid synthase (FAS), an enzyme that converts dietary carbohydrate to fat and that has only marginal importance in adults, but whose activity is essential for the proliferation and survival of most tumor cells. FAS is up-regulated in all the major solid tumors, and in most cases its expression is indicative of poor prognosis. The intent of this project is to develop a drug-like compound with nanomolar affinity for FAS that exhibits anti-tumor activity in vivo with a reasonable therapeutic index.

描述（由申请人提供）：预计将有50万人死于癌症，并在2008年被诊断出1,500,000人。因此，对新的抗癌药物有巨大的未满足医疗需求。这项研究将着重于开发针对脂肪酸合酶（FAS）的药物，这是将饮食中碳水化合物转化为脂肪的人类的唯一酶。 FA在成年人中仅具有边缘重要性，但其活性对于大多数肿瘤细胞的增殖和存活至关重要。在所有主要的实体瘤中，FA都在上调，在大多数情况下，其表达表明预后不良。有大量的证据，强调了FAS对肿瘤生长和生存的功能意义，并且证据表明其药理抑制作用可以预防体内肿瘤的生长。但是，尚无研究解决与将这些信息转化为人类健康改善的最重要问题：可以开发出可以发展出类似药物的FAS的小分子抑制剂，可以将其推进到临床前的发展中吗？这项研究的长期目标是通过以下特定目的解决这一主要问题：1）设计和合成FAS硫酯酶域的有效，选择性和可逆的小分子抑制剂。这些抑制剂将基于从筛选类似药物的化合物筛选文库中获得的命中，以及对酶的结构见解。 2）评估AIM 1中合成的化合物的效力和选择性； the FAS inhibitors will be assessed for (a) potency in assays measuring the catalytic activity of the recombinant thioesterase and the purified FAS holoenzyme, (b) for off-target effects against other human thioesterases, (c) cytotoxic potency against lipogenic and non-lipogenic tumor cells, (d) physicochemical and ADME/T properties using standard in vitro assays. 3）评估FAS的新型抑制剂用于抗肿瘤活性。将评估化合物的人乳腺癌和前列腺癌小鼠异种移植模型中肿瘤生长的能力。该项目的目的是提供具有对FA的纳摩尔亲和力的药物样化合物，该化合物在体内表现出抗肿瘤活性，并具有合理的治疗指数。 公共卫生相关性：这项研究的重点是开发针对脂肪酸合酶（FAS）的抗癌药，该酶将饮食中的碳水化合物转化为脂肪，仅在成年人中具有微不足道的重要性，但其活性对于大多数肿瘤细胞的增殖和存活至关重要。在所有主要的实体瘤中，FA都在上调，在大多数情况下，其表达表明预后不良。该项目的目的是开发具有对FA的纳摩尔亲和力的药物样化合物，该化合物在体内具有抗肿瘤活性，并具有合理的治疗指数。