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，在器官中 移植患者这些癌症的事件增加了10至250倍。 NMSC在 移植接受者的行为更具侵略性。因此，预防NMSC 移植患者是高度优先级。虽然类视黄素通常可以有效预防 NMSC，这些药物与严重的脂质毒性有关 长期给药。该计划项目的总体目的是确定潜力和 安全的雷克尼类似，并将其转化为预防NMSC的临床用途。要实现这一目标 目标，核心2将合成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个独立的结构性类别的rexinoids，它们是高度的 有效防止癌症而不增加脂质水平。这些新的例子 Rexinoids是UAB30，它也针对NMSC进行了测试，并且在临床前有效 防止NMSC的模型而不增加脂质水平。除了UAB30，第二 正在开发性类维生素类的结构类别，这些类别在癌症中也有效。 Core 2 Will 支持项目2、3和核心3通过为他们提供所需数量的UAB30和 UAB110。核心2还将合成新的第三代雷克尼，这是更重要的，并且 具有出色的安全性。拟议的新类似物将利用 UAB30和UAB110，并添加有限数量的副标士。安置的理由 副标士的基于我们的假设，即配体装订口袋中的“热点” 雷毒素对启动脂质生物合成很重要。在新的雷克尼素的设计中， 合成芯将采用X射线晶体学和量子机械计算。