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

• 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
• 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

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）：此R01申请名为“脂肪酸合酶的抑制剂抑制剂的铅优化”是针对PAR-12-060的Pars-12-060“征集验证的命运，以发现体内化学探针的发现”。现在，新陈代谢的重新生效被认为是癌症的标志之一，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（FASN）的表达和活性增加是许多肿瘤细胞的存活和增殖所必需的，包括前列腺，乳腺癌，结肠，卵巢，卵巢和肝脏。对于该提案而言，重要的是，最近在恶性黑色素瘤（一种威胁生命的皮肤癌形式）中确定了FASN的明确作用。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。最近，我们通过MLPCN程序筛选了FASN的360K化合物（TE）结构域，并确定了几个小分子命中，这些命中被证明是可拖动的。特别是，一个脚手架产生了一个具有有希望的体内特性的类似物。该系列中最先进的化合物是在体外的FASN-TE的有效且高度选择性的抑制剂，它阻止了整个细胞中的脂肪酸生物合成，停止肿瘤细胞增殖，在正常细胞中无毒性，并且在单个全身剂量（10 mg/kg i.p. i.p. i.p. i.p.）中显示出有希望的药物水平。然而，高蛋白结合，水溶性差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尺度化学优化，以提供准备体内概念验证研究的铅化合物。因此，我们的具体目的是：1。设计和合成在体内口服活性的优化FASN-TE抑制剂。 2。评估相关体外和细胞测定中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）测定法评估FASN-TE抑制剂。 4。确定铅FASN-TE抑制剂探针在相关小鼠肿瘤（异种移植）模型中的功效。产生的FASN-TE抑制剂将为测试FASN的抑制是杀死肿瘤细胞的有效方法，同时为未来开发新型的药物治疗癌症治疗的方法提供了有效的方法。