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.

抽象的： 非黑色素瘤皮肤癌（NMSC），其中包括基底细胞癌（BCC）和鳞状细胞癌 （SCC）是美国最常见的癌症类型之一。由于免疫力受损，固体器官 移植接受者（SOTR）的NMSC风险要高得多，并且通常成为死亡原因 sotrs。预防NMSC是理想的策略，特别是对于免疫受损人群而言。 rexinoids 是小分子药物，能够预防皮肤癌。但是，某些不良影响可能导致 不合规的使用。我们已经开发了两个不同类别的rexinoids结构：UAB30和 UAB20，具有高度选择性，无毒和口服的RXR激动剂。这些代理也很高 如我们的初步数据所示，有效预防皮肤癌。 UAB30和UAB20都不会导致 高脂血症，通常与临床批准的雷克内氏菌有关的作用。与癌症抑制相关 炎症生物标志物也是这些药物的吸引力。因此，我们对进一步的热情 作为癌症化学预防剂，开发这些药物的高效类似物促使我们提出 提交此建议。在X射线晶体学和生物物理研究的指导下，我们建议开发新型 与母体化合物相比，UAB30和UAB20具有增强效力的UAB30和UAB20的类似物，适用于药代动力学 长期给药，没有任何明显的毒性。 UAB30的低能分子构象很好地适合 RXR配体结合口袋（LBP）。我们的策略是显着提高效力，而不会扭曲 这两种药物的分子构象。因此，我们建议用A代替氢原子 卤素和/或杂原子。由于氟的电负性和碳氟的强度 债券，我们认为氟的战略引入将提高效力，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。诸如氮等杂原子可以 显着调节极性（LOGP）值。因此，我们提议替代 用氮的UAB30的四元环。单独和集体，这些修改将显着 有助于UAB30类似物的效力，并将其成为临床前评估的理想代理。相似地， 对于UAB20，X射线晶体结构表明，五个成员的杂环环更加容纳 有利，并在LBP内进行互动。因此，我们建议用 杂环环。这些修改还将调节日志并改善这些新的药代动力学 类似物。我们在此应用程序中的共同研究器开发了NMSC的独特鼠模型，该模型 在正常人群和SOTR中概述了该疾病的人类病理学。这些模型将是 在拟议的调查中使用，以定义适合慢性的最有效和无毒的类似物 NMSC化学预防。在此赠款期间，我们希望至少开发一个新的 Rexinoid准备在GLP毒性评估后进行临床发育。