Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals

开发作为抗炎剂和砷解毒剂的小分子抑制剂

基本信息

批准号：
10727507
负责人：
CORINNE ELIZABETH AUGELLI-SZAFRAN
金额：
$ 83.51万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727507
关键词：
Acids Anti-Inflammatory Agents Antidotes Arsenic Arsenicals Attenuated Binding Biological Assay Biological Availability British Bromodomain Bulla Cell Death Cells Chelating Agents Chemical Warfare Agents Chemicals Complex Computer software Cutaneous Cytochrome P450 DMSA Data Development Docking Drug Design Drug Kinetics Excretory function Exhibits Exposure to Funding Mechanisms Genes Goals Half-Life Hybrids IL-6 inhibitor IL6 gene In Vitro Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Interleukin-6 Laboratories Lead Mediating Metabolic Metabolism Microsomes Modeling Molecular Biology Mus Oral Organ Oxides Pain Pathway interactions Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphotransferases Play Poison Property Protein Family Protein Kinase Interaction Proteins RIPK1 gene RIPK3 gene Regulation Reporting Role Safety Series Skin Skin injury Solubility Specificity Structure Testing Therapeutic Therapeutic Index Tissues Toxic effect Vesicants Work absorption analog candidate identification cheminformatics chemokine computational chemistry cytokine cytotoxicity design drug development effective therapy efficacy evaluation experience high throughput screening improved in silico in vitro testing in vivo in vivo evaluation inhibitor lead candidate lead optimization lewisite machine learning model medical countermeasure member molecular modeling mouse model novel pre-clinical preclinical toxicity propylsulfonic acid response side effect skin damage small molecule inhibitor tool

项目摘要

Arsenicals cause rapid, severe and painful inflammatory and blistering responses in the skin. The available medical countermeasures against arsenical-induced toxicity are not effective due to toxicity and a low therapeutic index. Hence, there is a demand for the development of more effective and less toxic antidotes for arsenicals. Developing hybrid inhibitors of bromodomain-containing protein 4 (BRD4) which are responsible for the regulation of inflammatory genes, receptor-interacting protein kinase-3 (RIP3, or RIPK3), a central player in necroptosis, and interleukin-6 (IL-6) would be an effective and efficient treatment to attenuate arsenical-induced inflammation. We have identified three potent inhibitors, SRI-43887, SRI-47362 and SRI-47561 of BRD4, RIPK3 and IL6. For example, SRI-43887 exhibited significant activity in vivo against phenylarsine oxide (PAO) and arsenicals (Lewisite)-induced mice. Continued optimization of these compounds will lead to the identification of a potential preclinical candidate(s) for the treatment of cutaneous injuries associated with arsenicals. To achieve this goal, we will (i) utilize molecular modeling to design and synthesize analogs of these three lead compounds and test in vitro for BRD4, RIPK3 and IL6 inhibitory activity; (ii) evaluate select compounds for cytotoxicity and in vitro drug-like properties (solubility, metabolic stability, log D, permeability); (iii) determine the in vivo pharmacokinetic profile (bioavailability and half-life); and (iv) perform in vivo studies on select compounds against PAO and Lewisite to determine the efficacy of these compounds. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, biological assays, pharmacokinetics, molecular biology and drug development.

砷会引起皮肤快速、严重和痛苦的炎症和水泡反应。可用的由于毒性和治疗效果低，针对砷引起的毒性的医学对策并不有效指数。因此，需要开发更有效且毒性更低的砷解毒剂。开发含溴结构域蛋白 4 (BRD4) 的混合抑制剂，该抑制剂负责炎症基因受体相互作用蛋白激酶 3（RIP3 或 RIPK3）的调节，是炎症反应的核心参与者坏死性凋亡和白细胞介素 6 (IL-6) 将是减轻砷诱导的坏死性凋亡的有效且高效的治疗方法炎。我们已经鉴定出 BRD4、RIPK3 的三种有效抑制剂：SRI-43887、SRI-47362 和 SRI-47561 和IL6。例如，SRI-43887 在体内表现出显着的抗氧化苯胂 (PAO) 活性，砷（刘易斯）诱导的小鼠。这些化合物的持续优化将导致鉴定用于治疗与砷相关的皮肤损伤的潜在临床前候选药物。达到为了这个目标，我们将（i）利用分子模型来设计和合成这三种先导化合物的类似物并体外测试 BRD4、RIPK3 和 IL6 抑制活性； (ii) 评估选定化合物的细胞毒性和体外药物样特性（溶解度、代谢稳定性、log D、渗透性）； (iii) 确定体内药代动力学特征（生物利用度和半衰期）； (iv) 对选定的化合物进行体内研究 PAO 和 Lewisite 来确定这些化合物的功效。这些目标将通过一个在药物设计、药物化学、计算化学、生物测定、药代动力学、分子生物学和药物开发。