NOVEL ANTICANCER FATTY ACID SYNTHASE INHIBITORS

描述（由申请人提供）：癌症治疗的开发仍然是现代医疗保健的主要优先事项。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的和可能的选择性方法。史密斯小组最近发现，某些β-内酯（2-氧杂环丁酮，例如，奥利司他（Orlistat/R）抑制脂肪酸合成酶（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，因为脂肪酸代谢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，随后进行抑制FAS的生物学测试，预计将提供高度有效和选择性的拮抗剂。特别是，我们提出了一个组合的溶液/固相策略的平行合成奥利司他衍生物的开发与潜在的活性作为FAS拮抗剂。还提出了一种新的原位烯酮生成/二聚/氢化顺序，用于有效的两步合成作为潜在FAS拮抗剂的3，4-二取代β-内酯。将检测通过这些方法制备的β-内酯的活性，以确定其作为FAS及其重组硫酯酶结构域拮抗剂的效力和选择性。在进一步验证这些化合物在基于细胞的测定中作为FAS拮抗剂、细胞脂肪酸合成抑制剂、增殖、凋亡诱导剂的活性以及最终的选择性之后，将选择三至六种化合物用于在肿瘤生长的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的β-内酯拮抗剂的相互作用的假设，这些假设将通过分析待合成的新型β-内酯的结构-活性关系来进行测试。还将进行X射线晶体学研究，以确定FAS与奥利司他/R和同系物复合的三维结构。长期目标是鉴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）。

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).