Synthesis of Selective Inhibitors of Histone Methyltransferases as Potential Anti

描述（由申请人提供）：在本提案中，我讨论了组蛋白甲基转移酶（hmt）的重要性，特别是SUV39H1，以及它们在癌症治疗中的作用。该项目的长期目标是开发可能用于癌症化疗的SUV39H1抑制剂。SUV39H1的正常功能是组蛋白3的三甲基化赖氨酸9 (H3K9)，但在某些癌症中过度表达。在肿瘤抑制基因的启动子区域检测到癌细胞中H3K9的三甲基化，这使得抑制SUV39H1成为癌症化疗的可能策略。Larry Overman博士及其同事合成了一种化合物LEO-12-1406，该化合物含有一种epidithiodiketopiperazine （ETP）支架，是一种有效的、高选择性的SUV39H1抑制剂。目前，该ETP化合物与HMT的结合方式尚不清楚。Overman教授的合作者之一，John Williams博士（Beckman Research Institute, City of Hope）已经克隆出SUV39H1，并正在尝试用ETP类似物（如LEO-12-1406 bound）进行结晶。在获得这些x射线数据之前，我们依赖于Overman教授的另一位合作者（UCI制药科学系的David Mobley教授）构建的SUV39H1和LEO-12-1406的对接同源模型来预测可能的结合位点。利用这些模型，我提出了四种绑定假设。我将准备几个ETP类似物，经过生物学评估将表明这些断言是否准确。除了两个化合物外，LEO-12-1406类似物的合成将由五个步骤完成。该提案的另一个目标是合成谷氨酰胺A，这是一种ETP天然产物，将使我们能够探索另一种抑制HMT的支架。所概述的全部合成将在不到10步的时间内完成。一种有效的SUV39H1抑制剂的开发可能会改善某些癌症类型的治疗并改善患者的前景。类似地，谷胱甘肽A的合成将允许使用与目前提出的ETP类似物不同的支架获得类似物。

DESCRIPTION (provided by applicant): In this proposal, I discuss the importance of histone methyltransferases (HMTs), specifically SUV39H1, and their role in the treatment of cancer. The long-term goal of the project is to develop SUV39H1 inhibitors that could potentially be used for cancer chemotherapy. The normal function of SUV39H1 is to trimethylate lysine 9 of histone 3 (H3K9) but is overexpressed in some cancers. Trimethylation of H3K9 in cancer cells is detected at promoter regions of tumor suppressor genes, making inhibition of SUV39H1 a possible strategy for cancer chemotherapy. Dr. Larry Overman and co-workers have synthesized a compound, LEO-12-1406, with an epidithiodiketopiperazine (ETP) scaffold that is a potent and highly selective inhibitor of SUV39H1. Currently the binding mode of this ETP compound with the HMT is unknown. One of professor Overman's collaborators, Dr. John Williams (Beckman Research Institute, City of Hope) has cloned SUV39H1 and is attempting crystallization with ETP analogs such as LEO-12-1406 bound. Until this X-ray data is available, we are relying on docked homology models of SUV39H1 and LEO-12-1406 constructed by another collaborator of Professor Overman's (Professor David Mobley, UCI Department of Pharmaceutical Sciences) to predict possible binding sites. Using these models, I have posited four hypotheses of binding. I will prepare several ETP analogs that upon biological evaluation will indicate whether these assertions are accurate. With the exception of two compounds, the synthesis of LEO-12-1406 analogs will be accomplished by a five step sequence. The other objective of this proposal is the synthesis of glionitrin A, an ETP natural product that would allo us to explore another scaffold for HMT inhibition. The total synthesis as outlined would be accomplished in less than 10 steps. The development of a potent SUV39H1 inhibitor could potentially improve the treatment of some cancer types and improve outlook for patients. Similarly, the synthesis of glionitrin A would allow access to analogs with a different scaffold than the currently proposed ETP analogs.