NOVEL ANTICANCER FATTY ACID SYNTHASE INHIBITORS

新型抗癌脂肪酸合成酶抑制剂

• 批准号: 6759706
• 负责人: DANIEL ROMO
• 金额: $ 24.1万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-05 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6759706
• 关键词: X ray crystallography; active sites; antineoplastics; athymic mouse; chemical reaction; drug design /synthesis /production; enzyme inhibitors; fatty acid synthase; inhibitor /antagonist; ketene; lactones; neoplasm /cancer chemotherapy; protein structure function; stereochemistry; tissue /cell culture; water solubility

DESCRIPTION (provided by applicant): The development of therapies for cancer continues to be a major priority in modern day health care. In particular, therapies that focus on new protein targets can provide novel and possibly selective approaches to cancer chemotherapy. The recent finding by the Smith group that certain beta-lactones (2-oxetanones, e.g., Orlistat/R) inhibit the thioesterase (TE) domain of fatty acid synthase (FAS) provides a novel drug lead for cancer treatment as fatty acid metabolism has been linked to tumor onset and progression. Towards this end, the development and application of asymmetric methods for the synthesis of collections of structurally related beta-lactones and derivatives followed by their subsequent biological testing for inhibition of FAS is expected to provide highly potent and selective antagonists. In particular, we propose the development of a combination solution/solid phase strategy for the parallel synthesis of Orlistat derivatives with potential activity as FAS antagonists. Also proposed is a novel in situ ketene generation/dimerization/hydrogenation sequence for the efficient, two-step synthesis of 3,4-disubstituted beta-lactones as potential FAS antagonists. The activity of beta-lactones prepared by these methods will be tested for potency and selectivity in their ability to act as antagonists of FAS and its recombinant thioesterase domain. Following further verification of the activity of these compounds as FAS antagonists in cell-based assays, inhibitors of cellular fatty acid synthesis, proliferation, inducers of apoptosis, and finally selectivity, three to six compounds will be selected for testing in animal models of tumor growth. Based on the structure of Orlistat, we propose hypotheses regarding the interactions of beta-lactone antagonists of FAS that will be tested by analysis of structure-activity relationships of novel beta-lactones to be synthesized. X-ray crystallographic studies to determine the three dimensional structure of FAS in complex with Orlistat/R and congeners will also be undertaken. The long-term objective is to identify compound(s) that can be taken into pre-clinical development (i.e., pharmacokinetic analysis and extensive toxicity testing).

描述（由申请人提供）：癌症疗法的开发仍然是现代医疗保健的一个主要优先事项。特别是，专注于新蛋白质靶点的疗法可以为癌症化疗提供新颖且可能具有选择性的方法。 Smith 小组最近发现，某些 β-内酯（2-氧杂环丁酮，例如 Orlistat/R）可抑制脂肪酸合酶 (FAS) 的硫酯酶 (TE) 结构域，为癌症治疗提供了一种新的药物先导物，因为脂肪酸代谢已与肿瘤的发生和进展有关。为此，开发和应用不对称方法来合成结构相关的β-内酯和衍生物的集合，然后进行随后的抑制FAS的生物测试，预计将提供高效且选择性的拮抗剂。特别是，我们建议开发一种组合溶液/固相策略，用于平行合成具有 FAS 拮抗剂潜在活性的奥利司他衍生物。还提出了一种新颖的原位烯酮生成/二聚/氢化序列，用于高效、两步合成 3,4-二取代 β-内酯作为潜在的 FAS 拮抗剂。将测试通过这些方法制备的β-内酯作为FAS及其重组硫酯酶结构域的拮抗剂的效力和选择性的活性。在进一步验证这些化合物在细胞测定中作为 FAS 拮抗剂、细胞脂肪酸合成、增殖抑制剂、细胞凋亡诱导剂以及最终选择性的活性后，将选择三到六种化合物在肿瘤生长动物模型中进行测试。基于奥利司他的结构，我们提出了关于 FAS β-内酯拮抗剂相互作用的假设，这些假设将通过分析待合成的新型 β-内酯的结构-活性关系来测试。还将进行 X 射线晶体学研究，以确定 FAS 与 Orlistat/R 及其同系物复合物的三维结构。长期目标是确定可用于临床前开发的化合物（即药代动力学分析和广泛的毒性测试）。