Project 2: Design and Development of Third Generation RXR Rexinoids as Potential Chemoprevention Agents

项目 2：作为潜在化学预防剂的第三代 RXR Rexinoids 的设计和开发

• 批准号: 10263922
• 负责人: Matthew B Renfrow
• 金额: $ 13.11万
• 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/10263922
• 关键词: Address; Affect; Agonist; Anabolism; Basal cell carcinoma; Basic Science; Benchmarking; Bexarotene; Binding; Binding Sites; Biological Markers; Biophysics; Calorimetry; Canis familiaris; Chemopreventive Agent; Chronic; Clinical; Communication; Data; Deuterium; Development; Dose; Dose-Limiting; Effectiveness; Epidermis; Epithelial; Evaluation; Exhibits; FDA approved; Generations; Genes; Goals; Hot Spot; Human; Hydrogen; Hyperlipidemia; Immune; In Vitro; Inbred HRS Mice; Isomerism; Knowledge; Laboratories; Ligand Binding; Ligand Binding Domain; Lipids; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mass Spectrum Analysis; Modeling; Molecular; Molecular Profiling; Mus; Mutate; Names; Nuclear Receptors; Oral; Oral Administration; Organ Transplantation; Papilloma; Pathway interactions; Pharmaceutical Preparations; Phase; Population; Prevention; Preventive; Proteins; Publishing; RXR; Research Design; Retinoids; Rodent; Rodent Model; Series; Signal Transduction; Skin; Skin Carcinoma; Squamous cell carcinoma; Structural Biologist; Structure; Surface; Thermodynamics; Tissues; Titrations; Touch sensation; Toxic effect; Transgenic Mice; Transplant Recipients; Tretinoin; Ultraviolet B Radiation; United States; X-Ray Crystallography; biophysical analysis; cancer chemoprevention; cancer diagnosis; cancer prevention; clinical biomarkers; clinical development; design; high risk; high risk population; in vivo; in vivo Model; lead candidate; lipid biosynthesis; mouse model; mutant; novel; patient population; phase I trial; prevent; programs; receptor; recruit; research clinical testing; side effect; skin squamous cell carcinoma; targeted agent

Organ transplant patients who are immune-suppressed are at high risk to develop non-melanoma skin cancers (NMSC). Prevention of NMSC in this high risk population requires the development of effective drugs with minimal toxicity since these drugs are administered chronically. An FDA- approved drug has yet to be identified for use to prevent NMSC. We have developed a novel tissue-selective rexinoid, named UAB30, which acts as an agonist in epithelial tissues but not in liver. UAB30 is highly effective in multiple cancer prevention models while exhibiting minimal toxicity (especially lipid toxicity). UAB30 is currently evaluated in phase 1 human trials. Preliminary results (Core 3) show that UAB30 is highly effective in preventing the formation of papilloma, basal cell carcinoma, and squamous cell carcinoma in UVB-irradiated hairless mice. We have also shown that UAB30 up-regulates genes important for enhancing all-trans-retinoic acid biosynthesis in normal epithelium and in cancers. Thus, we hypothesize in this proposal that UAB30 (or other UAB30-like agonists) prevent NMSC by enhancing signaling through RXR-RAR heterodimers. In Aim 1, we propose studies to understand how rexinoids bind RXR and remodel the surface of the nuclear receptor to recruit coactivators. The importance of residues within the two putative molecular networks that bridge the rexinoid binding site to the coactivator binding site will be investigated using x-ray crystallography, Hydrogen-Deuterium Exchange Mass Spectrometry (HDX MS), and isothermal titration calorimetry (ITC). In Aim 2, we propose studies to understand if the molecular signatures of potency versus those of toxicity be revealed so that new 3rd -generation agonists are designed without toxicity. Structural studies on a series of methyl-derivatives of UAB30 have revealed a putative `hot-spot' in the ligand binding pocket that stimulates lipid biosynthesis and toxicity. We will examine the importance of this `hot-spot' by evaluating structures and dynamics of a series of potent rexinoids with known lipid profiles (potent rexinoids that induce lipid synthesis versus those that do not). A team of structural biologists with expertise in x-ray crystallography, mass spectrometry, thermodynamics, and biophysics has been assembled to address these aims. Project 2 provides information on the structure and dynamics of RXR, which we hypothesized, can be important for determining which rexinoids are potent and nontoxic. Project 2 will interact with Core 2 in designing new 3rd generation rexinoids, which will be evaluated in in vitro studies in Project 3 and in in vivo models in Core 3. The Program Integration section contains a complete developmental schema for 3rd generation rexinoids.

受到免疫抑制的器官移植患者的发展是高风险的高风险 皮肤癌（NMSC）。在这种高风险人群中预防NMSC需要发展 由于这些药物被长期服用，因此有效的有效药物具有最小的毒性。 FDA- 尚未确定用于预防NMSC的药物。我们已经开发了一本小说 组织选择性的旋转蛋白质，称为UAB30，在上皮组织中充当激动剂，但不在 肝。 UAB30在多种癌症预防模型中非常有效，同时表现最小 毒性（尤其是脂质毒性）。 UAB30目前在第1阶段的人类试验中进行了评估。 初步结果（核心3）表明，UAB30在防止形成方面非常有效 UVB辐照的无毛小鼠中的乳头状瘤，基底细胞癌和鳞状细胞癌。 我们还表明，UAB30上调基因，对于增强全反替诺剂很重要 正常上皮和癌症中的酸生物合成。因此，我们在这一提议中假设 UAB30（或其他UAB30样激动剂）通过通过RXR-RAR增强信号传导来防止NMSC 异二聚体。在AIM 1中，我们提出研究以了解雷克素如何结合RXR和重塑 核受体的表面募集共激活因子。残留物的重要性 两个推定的分子网络，桥接rexinoid结合位点与共激活因子结合 将使用X射线晶体学，氢 - 居民交换质量研究站点 光谱法（HDX MS）和等温滴定量热法（ITC）。在AIM 2中，我们建议研究 要了解是否会揭示效力与毒性的分子特征，以便 新的第三代激动剂的设计没有毒性。一系列的结构研究 UAB30的甲基衍生物已显示配体约束口袋中的一个假定的“热点” 刺激脂质生物合成和毒性。我们将研究此“热点”的重要性 评估具有已知脂质特征的一系列有效雷克尼素的结构和动力学（有效的 诱导脂质合成与不诱导脂质合成的rexinoids。一个结构生物学家团队与 X射线晶体学，质谱，热力学和生物物理学方面的专业知识已经 组装以解决这些目标。项目2提供有关结构和动态的信息 我们假设的RXR的RXR对于确定哪些雷克素有效，并且很重要 无毒。项目2将在设计新的第三代rexinoids时与Core 2互动，这将 在项目3和核心3中的体内模型中进行评估。 集成部分包含针对第三代rexinoids的完整发展模式。