Core 2: RXR Rexinoid Design and Synthesis

核心2：RXR Rexinoid设计与合成

• 批准号: 10263926
• 负责人: Venkatram Reddy Atigadda
• 金额: $ 12.83万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263926
• 关键词: Agonist; Basal cell carcinoma; Behavior; Benzene; Bexarotene; Binding; Binding Sites; Carbon; Chemistry; Chronic; Clinical; Crystallization; Crystallography; Data; Deuterium; Docking; Dose; Evaluation; Generations; Genetic Transcription; Goals; Grant; Hot Spot; Hybrids; Hydrogen; In Vitro; Incidence; Knowledge; Laboratories; Ligand Binding; Lipids; Malignant Neoplasms; Mechanics; Methods; Mind; Mus; Nuclear Receptors; Oncogenes; Organ Transplantation; Phase; Positioning Attribute; Pre-Clinical Model; Prevention; Preventive; Property; RXR; Research; Research Project Grants; Retinoids; Safety; Serum; Services; Signal Pathway; Signal Transduction; Skin; Skin Carcinoma; Squamous cell carcinoma; Structure; Testing; Tissues; Toxic effect; Translating; Transplant Recipients; Tretinoin; Triglycerides; Ultraviolet B Radiation; X-Ray Crystallography; analog; base; cancer chemoprevention; cancer prevention; combat; design; efficacy evaluation; experience; experimental study; improved; in vivo; in vivo evaluation; interest; knowledge base; lipid biosynthesis; lipophilicity; prevent; prevention evaluation; programs; quantum; research clinical testing; skin cancer prevention

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.

非黑色素瘤皮肤癌（NMSC）是最常见的皮肤恶性肿瘤和器官恶性肿瘤 移植患者这些癌症的发病率增加了10至250倍。NMSC在 移植受者的行为更具攻击性。因此，预防NMSC 移植病人是优先考虑的虽然类维生素A通常有效预防 NMSC，这些药物与严重的脂质毒性相关，因此排除了它们 慢性给药该计划项目的总体目标是确定一个有效的， 安全的rexinoid并将其转化为临床用于预防NMSC。为实现这一 为了实现这一目标，核心2将合成类Rexinoids，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了两种不同的rexinoids结构类型，它们高度 有效预防癌症而不增加脂质水平。这些新的例子之一 Rexinoids是UAB 30，它也正在接受针对NMSC的测试，并且在临床前有效 在不增加脂质水平的情况下预防NMSC的模型。除了UAB30，第二个 正在开发对癌症也有效的类维生素A结构类型。核心2将 支持项目2、3和核心3，向其提供所需数量的UAB 30， UAB 110。核心2还将合成新的第三代rexinoids，它们更有效， 安全性能极佳所提出的新类似物将利用以下结构模板： UAB 30和UAB 110，并添加有限数目的取代基。放置的理由 的取代基是基于我们的假设，即在配体结合口袋中的“热点”， rexinoid对启动脂质生物合成是重要的。在新的rexinoids的设计中， 合成核心将采用X射线晶体学和量子力学计算。