Drug Discovery for Fatty Acid Synthase in Oncology

描述（由申请人提供）：预计2008年将有50万人死于癌症，另有150万人将被诊断患有这种疾病。因此，对新的抗癌药物存在巨大的未满足的医疗需求。这项研究的重点是开发针对脂肪酸合成酶（FAS）的药物，FAS是人类唯一将饮食中的碳水化合物转化为脂肪的酶。FAS在成人中的重要性很小，但其活性对大多数肿瘤细胞的增殖和存活至关重要。FAS在所有主要实体瘤中均上调，并且在大多数情况下其表达指示不良预后。有大量证据强调FAS对肿瘤生长和存活的功能意义，并且有证据表明其药理学抑制可以防止体内肿瘤生长。然而，没有研究解决了与将这些信息转化为改善人类健康相关的最重要的问题：能否开发出一种可以进入临床前开发的药物样小分子FAS抑制剂？本研究的长期目标是通过以下具体目标来解决这一重大问题：1）设计和合成有效的、选择性的和可逆的FAS硫酯酶结构域的小分子抑制剂。这些抑制剂将基于从药物样化合物筛选文库中获得的命中，以及对酶的结构见解。2)评价目标1中合成的化合物的效力和选择性;将评估FAS抑制剂的（a）测定重组硫酯酶和纯化FAS全酶催化活性的试验中的效力，（B）对其他人硫酯酶的脱靶效应，（c）对脂肪生成和非脂肪生成肿瘤细胞的细胞毒性效力，（d）使用标准体外试验的理化和ADME/T特性。3)评价FAS的新型抑制剂的抗肿瘤活性。将评价化合物在人乳腺癌和前列腺癌的小鼠异种移植模型中减少肿瘤生长的能力。该项目的目的是递送对FAS具有纳摩尔亲和力的药物样化合物，其在体内表现出抗肿瘤活性，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成酶（FAS）的抗癌药物，FAS是一种将膳食碳水化合物转化为脂肪的酶，在成人中仅具有边缘重要性，但其活性对大多数肿瘤细胞的增殖和存活至关重要。FAS在所有主要实体瘤中均上调，并且在大多数情况下其表达指示不良预后。本项目的目的是开发一种对FAS具有纳摩尔亲和力的药物样化合物，其在体内表现出抗肿瘤活性，具有合理的治疗指数。

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.