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)，包括基底细胞癌 (BCC) 和鳞状细胞癌 （鳞状细胞癌）是美国最常见的癌症类型之一。由于免疫力下降，实体器官 移植受者 (SOTR) 患 NMSC 的风险要高得多，并且它常常成为患者的死亡原因 SOTR。预防 NMSC 是一种理想的策略，特别是对于免疫功能低下的人群。类Rexinoids 属于小分子药物，能够预防皮肤癌。然而，一些不利影响可能会导致 不遵守其使用规定。我们开发了两类不同类型的类毒素结构：UAB30 和 UAB20，是一种高选择性、无毒且口服生物可利用的 RXR 激动剂。这些代理也高 正如我们的初步数据所示，它可以有效预防皮肤癌。 UAB30 和 UAB20 均不会引起 高脂血症，这种效应通常与临床批准的类固醇相关。抑制癌症相关 炎症生物标志物也是这些药物的一个有吸引力的特性。因此，我们对进一步 开发这些药物的高效类似物作为癌症化学预防剂促使我们 提交此提案。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 UAB30 和 UAB20 的类似物，比母体化合物具有更强的效力，并具有适合的药代动力学 长期给药且无任何明显毒性。 UAB30 的低能分子构象非常适合 RXR 配体结合口袋 (LBP)。我们的策略是在不扭曲的情况下显着提高效力 这两种药物的分子构象。因此，我们建议将氢原子替换为 卤素和/或杂原子。由于氟的电负性和碳氟的强度 键，我们推断战略性地引入氟将提高效力、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。杂原子如氮可以 显着调节极性（logP）值。因此，我们建议用单碳替代 UAB30的四氢萘酮环带有一个氮。无论是单独还是集体，这些修改都将显着 有助于增强 UAB30 类似物的效力，并使它们成为临床前评估的理想药物。相似地， 对于UAB20，X射线晶体结构表明五元杂环容纳更多 有利地并在光体过程中进行互动。因此，我们建议将苯环取代为 杂环。这些修饰还将调节 logP 并改善这些新药物的药代动力学 类似物。我们的合作研究者在该应用中开发了独特的 NMSC 小鼠模型， 概括了正常人群和 SOTR 中该疾病的人类病理学。这些模型将 在拟议的研究中采用以确定适合慢性病的最有效和无毒的类似物 用于 NMSC 化学预防的给药。在此资助期内，我们预计将开发至少一种新的 在 GLP 毒性评估后，rexinoid 已准备好进行临床开发。