Core 2: RXR Rexinoid Design and Synthesis

摘要非黑色素瘤皮肤癌是最常见的皮肤及器官恶性肿瘤。 移植患者中，这些癌症的发病率增加了10到250倍。中国的NMSCs 移植受者的行为更具攻击性。因此，在中国预防NMSC 移植患者是一个高度优先的问题。虽然类维A酸类化合物通常在预防 NMSC，这些药物与严重的脂质毒性有关，因此排除了它们 长期给药。该计划项目的总体目标是确定一个有效和 安全的rexinate，并将其转化为临床用于预防NMSCs。为实现这一目标 目标，核心2将合成Rexinoid，以支持项目2、项目3和核心3的目标。 我们的实验室已经开发出两个独立的结构类别的rexinoid，这是高度 在不增加血脂水平的情况下有效预防癌症。这些新技术的一个例子 Rexinoids是UAB30，它也在针对NMSC进行测试，在临床前有效 在不增加血脂水平的情况下预防NMSC的模型。除了UAB30，第二个 维甲酸的结构类正在开发中，这种类维A酸对癌症也有效。核心2将 向项目2、3和核心3提供所需数量的UAB30和 UAB110。核心2还将合成新的第三代Rexinoid，它更有效和 拥有极佳的安全性能。拟议的新类比将利用以下结构模板 UAB30和UAB110，并添加有限数量的取代基。安置的理由是 是基于我们的假设，即配体结合口袋中的一个‘热点’ 类脂是启动脂质生物合成的重要物质。在新的rexinoid的设计中， 合成核心将使用X射线结晶学和量子力学计算。

Non-melanoma skin cancers (NMSCs) are the most common skin malignancy and in organ transplant patients the incidence of these cancers increase by 10 to 250 fold. The NMSCs in transplant recipients are more aggressive in behavior. Therefore, prevention of NMSC in transplant patients is a high priority. While retinoids are generally effective in prevention of NMSC, these agents are associated with severe lipid toxicities thus precluding them from chronic administration. The overall objective of the program project is to identify a potent and safe rexinoid and translate it into clinical use for prevention of NMSCs. Towards achieving this goal, Core 2 will synthesize rexinoids to support the aims of Project 2, Project 3 and Core 3. Our laboratory has developed two separate structural classes of rexinoids, which are highly effective in preventing cancers without increasing the lipid levels. One example of these new rexinoids is UAB30, which is also being tested against NMSC and is effective in preclinical models at preventing NMSC without increasing the lipid levels. In addition to UAB30, a second structural class of retinoids is being developed which are also effective in cancers. Core 2 will support projects 2, 3 and Core 3 by providing them with required quantities of UAB30 and UAB110. Core 2 will also synthesize new 3rd generation rexinoids which are more potent and have an excellent safety profile. The proposed new analogs will utilize structural templates of UAB30 and UAB110, and add a limited number of substituents. The rationale for the placement of the substituents is based on our hypothesis that a ‘hot-spot’ in the ligand binding pocket for the rexinoid is important to initiate lipid biosynthesis. In the design of new rexinoids, the Synthetic Core will employ x-ray crystallography, and quantum mechanical calculations.