Lead Optimization of Novel Inhibitors of the Thioesterase Domain of FASN

FASN 硫酯酶结构域新型抑制剂的先导化合物优化

基本信息

批准号：
8768420
负责人：
Nicholas David Cosford
金额：
$ 75.53万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8768420
关键词：
Acyl Carrier Protein Adult Adverse effects Apoptosis Binding Biological Assay Breast Carbon Cell Cycle Cell Proliferation Cells Cellular Assay Cessation of life Chemicals Chemistry Clinical Colon Complex Development Dietary Fats Disease Disease Progression Dose Drug Kinetics Drug usage Enzymes Family Fatty-acid synthase Foundations Future Growth In Vitro Laboratories Lead Libraries Life Link Liver Malignant Neoplasms Metabolic Metabolism Methods Mus Normal Cell Nutrient Ovary Palmitates Pathway interactions Pharmaceutical Preparations Physiology Pigments Positioning Attribute Property Prostate Protein Binding Reporting Resistance development Role Series Signal Transduction Skin Cancer Skin tanning Small Interfering RNA Solid Neoplasm Solubility Testing Therapeutic Therapeutic Agents Xenograft Model analog aqueous cancer therapy conventional therapy design fatty acid biosynthesis in vivo inhibitor/antagonist killings melanoma neoplastic cell novel novel strategies orlistat outcome forecast preclinical study programs public health relevance research study response scaffold screening small molecule tool tumor tumor metabolism tumor xenograft tumorigenic

项目摘要

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.

描述（由申请人提供）：这个题为“脂肪酸合酶硫酯酶域抑制剂的先导优化”的 R01 申请是对 PAR-12-060“体内化学探针发现的验证命中征集”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。实体瘤中的脂肪生成子网络通常上调，并且脂肪酸合酶（FASN）的表达和活性增加是许多肿瘤细胞（包括前列腺、乳腺癌、结肠、卵巢和肝脏）的生存和增殖所必需的。对于该提案来说重要的是，FASN 最近在恶性黑色素瘤（一种危及生命的皮肤癌）中发挥了明确的作用。因此，抑制 FASN 是治疗多种非常严重的癌症，尤其是黑色素瘤的有前途的方法。我们最近通过 MLPCN 程序针对 FASN 的硫酯酶 (TE) 结构域筛选了 360K 种化合物，并鉴定了几种被证明易于处理的小分子化合物。特别是，一个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 FASN-TE 体外有效且高度选择性的抑制剂，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，并在小鼠体内显示出有希望的药物水平单次全身剂量（10 mg/kg i.p.）。然而，高蛋白质结合、差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. 设计和合成具有口服体内活性的优化 FASN-TE 抑制剂。 2. 评估 FASN-TE 抑制剂在相关体外和细胞测定中的效力和选择性。 3. 使用体外 ADME/T 和体内药代动力学 (PK) 测定评估 FASN-TE 抑制剂。 4. 确定先导 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 抑制剂将为检验抑制 FASN 是杀死肿瘤细胞的有效方法这一假设提供强大的工具，同时为未来开发一类新型癌症治疗药物奠定基础。