Development of first-in-class antagonists of the retinoid pathway as novel oral therapies for Type 2 Diabetes

开发类视黄醇途径的一流拮抗剂作为 2 型糖尿病的新型口服疗法

基本信息

批准号：
10699637
负责人：
Mark Esposito
金额：
$ 33.76万
依托单位：
KAYOTHERA INC.
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：
2023-05-24 至 2025-05-23
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699637
关键词：
Achievement Affect Affinity Agonist Beta Cell Binding Biological Assay Biological Availability Blood Glucose Cell Differentiation process Cells Chemistry Clinical Clinical Trials Collaborations Communities Data Dedications Development Diabetes Mellitus Disease Dose Drug Combinations Drug Kinetics Enzymes Epidemic Exhibits Failure Family member Future Grant Head Health Hepatic Human Human Biology Hydrophobicity Hyperlipidemia Individual Insulin Lead Legal patent Ligands Metabolic Metabolic Diseases Modeling Modification Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Oral Oxidoreductase Pancreas Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Prevalence Program Development Property Proteins Publishing Regulatory Pathway Research Proposals Retinoids Rodent Route Safety Schedule Scientist Series Serum Signal Transduction Small Business Innovation Research Grant Specificity Structure Structure of beta Cell of islet Testing Tissues Toxicology Transcriptional Regulation Translating Tretinoin Type 2 diabetic Underserved Population Universities Vitamin A Work aldehyde dehydrogenases antagonist biomarker identification candidate selection cell dedifferentiation cross reactivity db/db mouse diabetic dietary drug development drug discovery early phase clinical trial efficacy testing experimental study glucagon-like peptide 1 improved in vivo inhibitor innovation insight insulin secretion insulin sensitivity interest lead candidate lead optimization marginalized population mouse model new therapeutic target next generation novel novel therapeutics oxidation pharmacodynamic biomarker pharmacokinetics and pharmacodynamics pharmacologic preclinical efficacy receptor research and development research clinical testing restoration retinoic acid receptor alpha scaffold secondary endpoint synergism therapy outcome tool treatment effect

项目摘要

Project Summary: The retinoid pathway is a central regulatory pathway in human biology that has been considered undruggable for the last 20 years. It is activated when dietary vitamin A is transported to target tissues, is oxidized to all-trans retinoic acid (atRA), and then binds the RARα/β/γ nuclear receptors. This binding results in transcriptional regulation that is best known to influence the differentiation state of various cells and tissues. In metabolic disorders, ALDH1a3 is a key enzyme responsible for the final synthetic step of the retinoid ligand, and has also been identified as one of the principal pancreatic β cell markers for Type 2 diabetes. Numerous studies have shown that ALDH1a3 protein levels or enzymatic activity is a specific marker for failing/dedifferentiated β cells that lose the ability to produce insulin in Type 2 diabetics. Whereas retinoid signaling has long been a pathway of interest in both rodent and human diabetes, published studies have not established whether or not retinoid signaling and thus ALDH1a3 are drivers of Type 2 diabetes. Our initial discovery work suggests that ALDH1a3 is a driver of the β cell dedifferentiation observed in Type 2 diabetes and thus may offer a target whose inhibition can offer durable treatment effects for diabetics. Discussions with stakeholders across the Type 2 Diabetes community have demonstrated considerable interest in disease-modifying therapies that restore pancreatic function as there is broad recognition that current therapies are limited in activity to controlling blood glucose levels and insulin sensitivity rather than affecting pancreatic health. Thus, to reverse the projected rise of Type 2 diabetics across the world, next generation drug combinations are needed that restore pancreatic β cells to their normal differentiation status. Utilizing proprietary chemistry platforms, Kayothera is the first group to have developed lead inhibitors against ALDH1a3 that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs in the retinoid pathway. Our therapies show strong potency in inhibiting the retinoid pathway (<5 nM cellular, a 200-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate an IND development candidate through dose-range finding studies and PD/efficacy models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of restoring pancreatic health to millions of patients in need.

项目概要：类维生素A途径是人类生物学中的一个中心调节途径，已被认为在过去 20 年中，当饮食中的维生素 A 被输送到目标组织时，它就会被激活。被氧化为全反式视黄酸（atRA），然后与 RARα/β/γ 核受体结合。导致转录调控，最著名的是影响各种细胞的分化状态在代谢紊乱的细胞和组织中，ALDH1a3 是负责最终合成的关键酶。类维生素A配体的步骤，也被确定为主要的胰腺β细胞标记物之一大量研究表明 ALDH1a3 蛋白水平或酶活性与 2 型糖尿病有关。 2 型细胞丧失产生胰岛素能力的衰竭/去分化 β 细胞的特定标记除了类维生素A信号传导长期以来一直是啮齿动物和人类感兴趣的途径。糖尿病，已发表的研究尚未确定视黄醇信号传导是否与 ALDH1a3 是 2 型糖尿病的驱动因素。我们的初步发现工作表明 ALDH1a3 是 β 细胞去分化的驱动因素在 2 型糖尿病中观察到，因此可能提供一个目标，通过抑制该目标可以提供持久的治疗与 2 型糖尿病社区的利益相关者进行的讨论人们对恢复胰腺功能的疾病缓解疗法非常感兴趣人们普遍认识到，目前的疗法在控制血糖水平方面的作用有限和胰岛素敏感性而不是影响胰腺健康，从而扭转 Type 的预期上升。全球 2 名糖尿病患者需要下一代药物组合来恢复胰腺β 使细胞恢复正常的分化状态。 Kayothera 利用专有的化学平台，是第一个开发出铅的集团针对 ALDH1a3 的抑制剂显示出卓越的效力和特异性，同时避免了我们的疗法中其他药物开发项目的药理作用。显示出强大的抑制类视黄醇途径的效力（<5 nM 细胞，比已发表的分子），无脱靶活性，代谢稳定性高，口服药代动力学优异特性和有前景的体内毒理学在这里，我们建议提名一项 IND 开发。通过剂量范围寻找研究和 PD/功效模型的候选者。该提案将推动一流疗法走向临床测试，旨在恢复胰腺功能为数百万有需要的患者带来健康。