Core 2: RXR Rexinoid Design and Synthesis

核心2：RXR Rexinoid设计与合成

基本信息

批准号：
10007603
负责人：
Venkatram Reddy Atigadda
金额：
$ 20.18万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10007603
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

项目摘要

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的 NMSC 中这些癌症的发病率增加 10 至 250 倍。移植受者的行为更具攻击性，因此，预防 NMSC 的发生。移植患者是重中之重，而类维生素A通常可以有效预防。 NMSC，这些药物与严重的脂质毒性有关，因此阻止它们该计划项目的总体目标是确定一个有效的和长期的管理。安全的 rexinoid 并将其转化为预防 NMSC 的临床用途。为了实现目标，核心 2 将合成 rexinoids 以支持项目 2、项目 3 和核心 3 的目标。我们的实验室开发了两种不同结构类别的类毒素，它们具有高度的这些新产品的一个例子是在不增加脂质水平的情况下有效预防癌症。 rexinoids 是 UAB30，也正在针对 NMSC 进行测试，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 之外，还有第二个模型。正在开发的类视黄醇结构类别对癌症也有效。通过向项目 2、3 和核心 3 提供所需数量的 UAB30 和 UAB110.Core 2还将合成新的第三代rexinoids，其更有效且更有效。具有出色的安全性。拟议的新类似物将利用结构模板。 UAB30和UAB110，并添加有限数量的取代基放置的理由。取代基的分布基于我们的假设，即配体结合口袋中的“热点” rexinoid 对于启动脂质生物合成很重要在新的 rexinoid 的设计中，合成核心将采用 X 射线晶体学和量子力学计算。