Lead Optimization of Novel Inhibitors of the Thioesterase Domain of FASN

描述（由申请人提供）：该R01申请名为“脂肪酸合成酶硫酯酶结构域抑制剂的先导优化”，是对PAR-12-060“体内化学探针发现的有效靶点征集”的回应。代谢重新布线现在被认为是癌症的标志之一，可以在许多中央碳代谢的子网络中观察到。脂质生成子网络在实体肿瘤中经常上调，脂肪酸合成酶（FASN）的表达和活性增加是许多肿瘤细胞（包括前列腺、乳腺、结肠、卵巢和肝脏）存活和增殖所必需的。重要的是，FASN在恶性黑色素瘤（一种危及生命的皮肤癌）中的明确作用最近得到了证实。因此，抑制FASN是治疗多种非常严重的癌症，特别是黑色素瘤的一种很有前途的方法。我们最近通过MLPCN程序筛选了360K种针对FASN硫酯酶（TE）结构域的化合物，并确定了几个被证明是可处理的小分子命中。特别是，一种支架产生了一系列具有良好体内特性的类似物。该系列中最先进的化合物是体外有效的高选择性FASN-TE抑制剂，可阻断全细胞中的脂肪酸生物合成，阻止肿瘤细胞增殖，对正常细胞无毒，单次全身剂量（10 mg/kg i.p.）后在小鼠中显示出有希望的药物水平。然而，高蛋白质结合、低水溶性和低微粒体稳定性表明，必须优化药代动力学特性，以提供适合体内概念验证实验的化合物。这些化合物已准备好进行全面的化学优化，为体内概念验证研究提供先导化合物。因此，我们的具体目标是：1。设计并合成经优化的FASN-TE体内口服活性抑制剂。2. 在相关的体外和细胞试验中评估FASN-TE抑制剂的效力和选择性。3. 使用体外ADME/T和体内药代动力学（PK）分析评估FASN-TE抑制剂。4. 确定FASN-TE抑制剂铅探针在相关小鼠肿瘤（异种移植）模型中的作用。所产生的FASN- te抑制剂将为验证抑制FASN是杀死肿瘤细胞的有效方法这一假设提供强有力的工具，同时为未来开发一类新型癌症治疗药物奠定基础。

DESCRIPTION (provided by applicant): This R01 application entitled "Lead Optimization of Inhibitors of the Thioesterase Domain of Fatty Acid Synthase" is in response to PAR-12-060 "Solicitation of Validated Hits for the Discovery of in vivo Chemical Probes". Metabolic re-wiring is now recognized as one of the hallmarks of cancer and can be observed in many sub-networks of central carbon metabolism. The lipogenic sub-network is often up-regulated in solid tumors, and increased expression and activity of fatty acid synthase (FASN) is required for the survival and proliferation of many tumor cells, including prostate, breast, colon, ovaries, and liver. Importantly for this proposal, a clear role for FASN has recently been established in malignant melanoma, a life-threatening form of skin cancer. Thus, inhibition of FASN is a promising approach for the treatment of multiple very serious forms of cancer, and especially melanoma. We recently screened 360K compounds against the thioesterase (TE) domain of FASN through the MLPCN program and identified several small molecule hits that proved to be tractable. In particular, one scaffold yielded a family of analogues with promising in vivo properties. The most advanced compound from this series is a potent and highly selective inhibitor of FASN-TE in vitro, blocks fatty acid biosynthesis in whole cells, halts tumor cell proliferation, is non-toxic in normal cells, and shows promising drug levels in mice following a single systemic dose (10 mg/kg i.p.). However, high protein binding, poor aqueous solubility and low microsomal stability suggest that the pharmacokinetic properties must be optimized to provide compounds suitable for in vivo proof-of-concept experiments. These compounds are ready for full- scale chemistry optimization to provide lead compounds ready for in vivo proof-of-concept studies. Therefore our Specific Aims are: 1. Design and synthesize optimized FASN-TE inhibitors that are orally active in vivo. 2. Assess potency and selectivity of FASN-TE inhibitors in relevant in vitro and cellular assays. 3. Evaluate FASN-TE inhibitors using in vitro ADME/T and in vivo pharmacokinetic (PK) assays. 4. Determine efficacy of lead FASN-TE inhibitor probes in relevant mouse tumorigenic (xenograft) models. The FASN-TE inhibitors generated will provide powerful tools for testing the hypothesis that inhibition of FASN is an effective method for killing tumor cells, while laying a foundation for future development of a novel class of medications for the treatment of cancer.