Developing novel therapeutics for the treatment of mastocytosis

开发治疗肥大细胞增多症的新疗法

基本信息

批准号：
10480408
负责人：
Jianya Peng
金额：
$ 25.21万
依托单位：
NEMAGEN DISCOVERIES, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480408
关键词：
Abdominal Pain Address Anaphylaxis Anemia Antihistamines Biological Assay C-KIT Mutation Carbonic Anhydrase Inhibitors Cell Line Cells Characteristics Chronic Dangerousness Data Development Disease Dose Enzyme Inhibitor Drugs Enzymes Foundations Headache Histamine Production Histamine Release Human In Vitro Inflammation Inflammation Mediators Lead Letters Leukotrienes Life Lung Mast Cell Stabilizer Mediating Methods Modeling Motivation Mus Muscle Contraction Mutation Organ Patient Care Patients Pharmaceutical Chemistry Pharmacotherapy Phase Physicians Population Production Prostaglandins Proto-Oncogene Protein c-kit Pruritus Publishing Rare Diseases Skin Small Business Innovation Research Grant Smooth Muscle Societies Stimulus Study models Surface Surveys Symptoms System Testing Tissues Urticaria base carbonate dehydratase care providers common symptom computational chemistry design drug candidate effective therapy enzyme activity falls improved in vivo in vivo Model inhibitor mast cell mastocytosis mouse model nanomolar nature therapy new therapeutic target novel novel therapeutics pathogen patient population physical property preclinical study prevent process optimization programs protein data bank protein structure receptor response side effect small molecule stem cells targeted treatment translational applications treatment strategy

项目摘要

Abstract Mastocytosis is a term used to describe a set of rare diseases that are characterized by increased mast cell development and the enhanced presence of mast cells in various tissues and organs. Once activated, mast cells promote inflammation through their robust production of histamines, leukotrienes, prostaglandins and many other effector molecules that promote itching, burning, smooth muscle contraction and life-threatening anaphylaxis, all of which are common symptoms of mastocytosis. Although patients suffering from mastocytosis are prescribed antihistamines and mast cell stabilizers, treatment options are limited, and more severe forms of the disease are extremely difficult to treat and remain life-threatening. Further, an incomplete understanding of the factors that regulate mast cell development has dramatically limited the ability to design novel therapeutics that selectively target mast cells. NemaGen’s published and preliminary studies have revealed that the enzyme carbonic anhydrase (Car)1 is exclusively expressed by mast cell progenitors. Further, we have demonstrated that small molecule-mediated inhibition of Car1 is sufficient to prevent murine and human mast cell development. In addition, our data demonstrate that in vivo treatment with known carbonic anhydrase inhibitors is sufficient to prevent mast cell development and inflammation in a murine model of mastocytosis. Collectively, these studies suggest that Car1 represents a novel therapeutic target for the treatment of mastocytosis and mast cell-mediated inflammation. Although existing carbonic anhydrase inhibitors are available, our studies have shown that their effective doses far exceed those required for translational applications. To address this, we have generated a strong team and effective workflow that allows us to synthesize and test new Car enzyme inhibitors. Further, our data demonstrate that we can generate significantly more effective inhibitors than currently available options. These exciting findings form the foundation of this SBIR proposal and two specific aims: (i) Design, synthesize and optimize novel carbonic anhydrase inhibitors. (ii) Evaluate the effects of Car enzyme inhibitors on enzymatic function and mast cell development both in vitro and in vivo. Collectively, these pre-clinical studies will allow us to generate new Car enzyme inhibitors for the treatment of mastocytosis and other mast cell-related disorders.

抽象的肥大细胞增多症是用于描述一组稀有疾病的术语，这些疾病的特征是肥大细胞增加在各种时序和器官中的发育和增强肥大细胞的存在。一旦激活，桅杆细胞通过强大的组胺，白三烯，前列腺素和许多其他效应子分子促进瘙痒，燃烧，平滑肌收缩和威胁生命过敏反应，所有这些都是肥大症的常见症状。虽然患者患有肥大细胞增多是处方抗组胺药和肥大细胞稳定剂，治疗选择有限，更多严重的疾病形式极为难以治疗和威胁生命。此外，一个不完整了解调节肥大细胞发育的因素已极大地限制了设计新颖的疗法，有选择地靶向肥大细胞。 Nemagen的出版和初步研究已经揭示了酶碳酸酐酶（CAR）1仅由肥大细胞祖细胞表达。此外，我们已经证明了小分子介导的car1抑制足以防止鼠和人类肥大细胞的发育。此外，我们的数据表明，体内治疗已知碳酸酐酶抑制剂足以防止肥大细胞的发育和注射总的来说，这些研究表明CAR1代表了一个新型的热目标肥大细胞增多症和肥大细胞介导的注射的治疗。虽然现有的碳酸酐酶可以使用抑制剂，我们的研究表明，它们的有效剂量远远超过翻译应用。为了解决这个问题，我们建立了一个强大的团队和有效的工作流程，可以我们要合成和测试新的汽车酶抑制剂。此外，我们的数据表明我们可以生成比当前可用的选项要高得多的抑制剂。这些令人兴奋的发现形成了该SBIR提案的基础和两个具体目标：（i）设计，合成和优化新颖的碳赤道酶抑制剂。（ii）评估CAR酶抑制剂对酶功能和肥大细胞的影响在体外和体内发育。总的来说，这些临床前研究将使我们能够生成新车酶抑制剂用于治疗肥大细胞增多症和其他肥大细胞相关疾病。