NOVEL ANTICANCER FATTY ACID SYNTHASE INHIBITORS

描述(由申请人提供)：癌症治疗方法的发展仍然是现代医疗保健的主要优先事项。特别是，专注于新的蛋白质靶点的疗法可以为癌症化疗提供新的、可能是选择性的方法。Smith小组最近发现，某些β-内酯(2-氧杂环酮，如奥利斯特/R)抑制脂肪酸合成酶(Fas)的硫酯酶(TE)结构域，这为治疗癌症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发展有关。为此，开发和应用不对称方法来合成结构上相关的β-内酯及其衍生物，然后对其进行抑制Fas的生物测试，有望提供高度有效和选择性的拮抗剂。特别是，我们建议开发一种溶液/固相相结合的策略来平行合成具有潜在Fas拮抗剂活性的奥利司他衍生物。还提出了一种新的原位生成/二聚/氢化序列，用于高效、两步合成潜在的Fas拮抗剂3，4-二取代β-内酯。用这些方法制备的β-内酯类化合物的活性将被测试它们作为Fas及其重组硫酯酶结构域的拮抗剂的效力和选择性。在进一步验证了这些化合物在基于细胞的分析中作为Fas拮抗剂、细胞脂肪酸合成、增殖、凋亡诱导剂以及最终选择性的活性后，将选择3至6个化合物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-内酯拮抗剂相互作用的假说，这些假说将通过分析将要合成的新型β-内酯的构效关系来检验。还将进行X射线结晶学研究，以确定Fas与奥利司他/R及其同系物形成的络合物的三维结构。长期目标是确定可用于临床前开发(即药代动力学分析和广泛的毒性测试)的化合物(S)。

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).