Lead Optimization of Novel Inhibitors of the Thioesterase Domain of FASN

描述（由申请人提供）：本R 01申请题为“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“用于发现体内化学探针的验证命中请求”的回应。代谢重新布线现在被认为是癌症的标志之一，并且可以在中央碳代谢的许多子网络中观察到。脂肪生成子网络通常在实体瘤中上调，并且脂肪酸合酶（FATCH）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）的存活和增殖所需的。对于这项提议来说，重要的是，最近已经确定了FRENTA在恶性黑色素瘤（一种危及生命的皮肤癌）中的明确作用。因此，抑制FXR是治疗多种非常严重形式的癌症，特别是黑色素瘤的有希望的方法。我们最近通过MLPCN程序筛选了360 K化合物，针对Festival的硫酯酶（TE）结构域，并鉴定了几种被证明是易处理的小分子命中物。特别是，一个支架产生了一个家庭的类似物有前途的体内性能。该系列中最先进的化合物是体外FASN-TE的有效和高选择性抑制剂，阻断全细胞中的脂肪酸生物合成，阻止肿瘤细胞增殖，在正常细胞中无毒，并且在单次全身剂量（10 mg/kg i. p.）后在小鼠中显示出有希望的药物水平。然而，高蛋白结合、差的水溶性和低微粒体稳定性表明必须优化药代动力学性质以提供适合于体内概念验证实验的化合物。这些化合物准备好进行全面的化学优化，以提供准备好进行体内概念验证研究的先导化合物。因此，我们的具体目标是：1。设计和合成优化的FASN-TE抑制剂，其在体内具有口服活性。2.在相关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）试验评价FASN-TE抑制剂。4.确定前导FASN-TE抑制剂探针在相关小鼠致瘤（异种移植）模型中的功效。所产生的FASN-TE抑制剂将为测试抑制FASN-TE是杀死肿瘤细胞的有效方法的假设提供强大的工具，同时为未来开发用于治疗癌症的新型药物奠定基础。

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.