Development of Potent and non-toxic rexinoids to prevent non-melanoma skin cancer

开发有效且无毒的类毒素来预防非黑色素瘤皮肤癌

• 批准号: 10562891
• 负责人: Venkatram Reddy Atigadda
• 金额: $ 61.01万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562891
• 关键词: Acidity; Adverse effects; Agonist; American Cancer Society; Animals; Apoptosis; Basal cell carcinoma; Bexarotene; Binding; Biological Availability; Biological Markers; Calorimetry; Cancer Biology; Cancer Model; Carbon; Carboxylic Acids; Cause of Death; Cell Respiration; Chemopreventive Agent; Chronic; Clinical; Complex; Cutaneous Lymphoproliferative Disorder; Data; Development; Disease; Dose; Drug Kinetics; Economic Burden; Emotional; Evaluation; FDA approved; Fluorine; Genetic Transcription; Grant; Half-Life; Halogens; Homo; Human; Hydrogen; Hyperlipidemia; Immune; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Investigation; Isotretinoin; Laboratories; Ligand Binding; Lipids; Liver X Receptor; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Metabolic; Modeling; Modification; Molecular Conformation; Nitrogen; Nuclear Receptors; Oral; Organ Transplantation; Parents; Peptides; Pharmaceutical Preparations; Play; Polyenes; Population; Prevention; Prevention strategy; Preventive; Proliferating; Property; Proteins; RXR; Research Personnel; Retinoic Acid Receptor; Retinoids; Roentgen Rays; Role; Safety; Serum; Skin; Skin Carcinogenesis; Skin Carcinoma; Solid; Squamous cell carcinoma; Structure; Surface; Tetralones; Titrations; Toxic effect; Translating; Translations; Transplant Recipients; Tretinoin; UVB induced; X-Ray Crystallography; alitretinoin; analog; biophysical analysis; cancer chemoprevention; cancer diagnosis; cancer type; clinical candidate; clinical development; combat; design; experimental study; high risk; human model; improved; innovation; lipophilicity; member; metabolic profile; mouse model; non-compliance; novel; organ transplant recipient; pharmacologic; phase 1 study; pre-clinical; preclinical development; preclinical evaluation; prevent; prospective; receptor; recruit; side effect; skin cancer prevention; skin lesion; small molecule; time interval; tissue biomarkers; water solubility

Abstract: Non-melanoma skin cancer (NMSC), which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is one of the most common types of cancers in the US. Due to compromised immunity, solid organ transplant recipients (SOTRs) are at a much higher risk for NMSC and it often becomes the cause of death in SOTRs. Prevention of NMSC is an ideal strategy, particularly for immune compromised populations. Rexinoids are small molecule drugs and are able to prevent skin cancer. However, some of the adverse effects may lead to non-compliance in their use. We have developed two distinct classes of structures of rexinoids: UAB30 and UAB20, which are highly selective, non-toxic and orally bioavailable RXR agonists. These agents are also highly effective in preventing skin cancer as shown in our preliminary data. Both UAB30 and UAB20 do not cause hyperlipidemia, an effect usually associated with clinically approved rexinoids. Dampening cancer associated inflammatory biomarkers is also an attractive property of these agents. Thus, our enthusiasm for further developing highly effective analogs of these agents as cancer chemopreventive agents has prompted us to submit this proposal. Guided by x-ray crystallography and biophysical studies, we propose to develop novel analogs of UAB30 & UAB20 with enhanced potency than parent compounds, with suitable pharmacokinetics for chronic administration and without any overt toxicity. Low energy molecular conformation of UAB30 fit well into the RXR ligand-binding pocket (LBP). Our strategy is to improve the potency significantly without distorting the molecular conformations of these two agents. Therefore, we propose to substitute a hydrogen atom with a halogen and/or a heteroatom. Because of the electronegativity of fluorine and the strength of carbon-fluorine bond, we have reasoned that strategic introduction of fluorine will improve the potency, oral bioavailability, metabolic stability and pharmacokinetics of the newly synthesized analogs. Heteroatoms such as nitrogen can modulate the polarity (logP) value significantly. Therefore, we have proposed to substitute a single carbon of tetralone ring of the UAB30 with a nitrogen. Individually and collectively, these modifications will significantly contribute to the potency of UAB30 analogs and will make them ideal agents for pre-clinical evaluation. Similarly, for UAB20, x-ray crystal structures reveal that a five membered heterocyclic ring is accommodated more favorably and make interactions within the LBP. Therefore, we have proposed to substitute the phenyl ring with heterocyclic rings. These modifications will also modulate the logP and improve pharmacokinetics of these new analogs. Our co-investigator in this application has developed unique murine models of the NMSC, which recapitulate human pathobiology of the disease both in normal population and in SOTRs. These models will be employed in the proposed investigations to define the most effective and non-toxic analogs suitable for chronic administration for NMSC chemoprevention. During this grant period, we expect to develop at least one new rexinoid ready for clinical development after GLP toxicity evaluation.

摘要： 非黑色素瘤皮肤癌(NMSC)，包括基底细胞癌(BCC)和鳞癌 鳞癌是美国最常见的癌症类型之一。由于免疫力受损，坚固的器官 移植受者患NMSC的风险要高得多，它通常会成为#年的死亡原因。 SOR。预防NMSC是一个理想的策略，特别是对于免疫受损的人群。雷克西诺类化合物 是小分子药物，能够预防皮肤癌。然而，一些不良影响可能会导致 在使用过程中不遵守规定。我们已经开发出两类不同的rexinoid结构：UAB30和UAB30 UAB20，这是高度选择性、无毒和口服生物利用的RXR激动剂。这些特工也高度 我们的初步数据显示，它在预防皮肤癌方面有效。UAB30和UAB20都不会导致 高脂血症，这种效应通常与临床批准的类维A酸类药物有关。与抑制癌症相关 炎性生物标记物也是这些药物的一个吸引人的特性。因此，我们对进一步发展的热情 开发这些药物的高效类似物作为癌症化学预防药物促使我们 提交此建议书。在x射线结晶学和生物物理研究的指导下，我们建议开发新的 UAB30和UAB20的类似物具有比母体化合物更强的效力，具有合适的药物动力学。 长期给药，无任何明显毒性。UAB30的低能分子构象很好地符合 RXR配体结合口袋(LBP)。我们的策略是在不扭曲 这两种试剂的分子构象。因此，我们建议用氢原子取代氢原子 卤素和/或杂原子。由于氟的电负性和碳-氟的强度 邦德，我们的理由是，战略引入氟将提高效力，口服生物利用度， 新合成类似物的代谢稳定性和药代动力学。氮等杂原子可以 显著调制极性(LogP)值。因此，我们建议用一种单一的碳 带有氮气的UAB30的四龙环。无论是单独还是集体，这些修改都将显著 有助于UAB30类似物的效力，并将使它们成为临床前评估的理想药物。同样， 对于UAB20，X-射线晶体结构表明，五元杂环被更多地容纳 有利的，并在LBP内部进行互动。因此，我们建议用苯环取代苯环 杂环环。这些修饰还将调节logP并改善这些新药物的药代动力学 类比。我们在这项应用中的合作研究员开发了独特的NMSC小鼠模型，它 概述人类在正常人群和SOR中的疾病病理生物学。这些模型将是 在拟议的研究中使用，以确定最有效和无毒的类似物适合慢性 NMSC化学预防管理局。在此授权期内，我们预计将开发至少一个新的 经过GLP毒性评估后，Rexin可用于临床开发。