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150万人被诊断出患有癌症。因此，对新的抗癌药物存在巨大的未满足的医疗需求。这项研究将专注于开发对抗脂肪酸合成酶（FAS）的药物，这是人类唯一一种将饮食中的碳水化合物转化为脂肪的酶。FAS在成人中作用不大，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，其表达在多数情况下预示预后不良。大量证据表明，FAS对肿瘤生长和存活具有重要的功能意义，其药理抑制作用可在体内抑制肿瘤生长。然而，没有一项研究解决了将这些信息转化为改善人类健康的最重要问题：能否开发出一种类似药物的FAS小分子抑制剂，并将其推进到临床前开发？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FAS硫酯酶结构域的有效，选择性和可逆的小分子抑制剂。这些抑制剂将基于从药物样化合物的筛选文库中获得的命中点，以及对酶的结构见解。2)评价Aim 1中合成的化合物的效价和选择性；FAS抑制剂将进行以下评估：(a)重组硫酯酶和纯化FAS全酶催化活性测定中的效力，(b)针对其他人类硫酯酶的脱靶效应，(c)针对脂肪生成和非脂肪生成肿瘤细胞的细胞毒性，(d)使用标准体外测定的理化和ADME/T特性。3)评价新型FAS抑制剂的抗肿瘤活性。这些化合物将被评估在人类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。本项目的目的是提供一种具有纳米级FAS亲和力的药物样化合物，在体内具有抗肿瘤活性，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.