Developing novel therapeutics for the treatment of mastocytosis

开发治疗肥大细胞增多症的新疗法

• 批准号: 10742448
• 负责人: Jianya Peng
• 金额: $ 5.5万
• 依托单位: NEMAGEN DISCOVERIES, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2023-04-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10742448
• 关键词: Abdominal Pain; Acceleration; Address; Anaphylaxis; Capital; Carbon Dioxide; Carbonic Anhydrase Inhibitors; Cellular biology; Complement; Development; Disease; Doctor of Philosophy; Enzyme Inhibitor Drugs; Enzymes; Face; Family; Foundations; Funding; Grant; Health; Homeostasis; Human; Industry; Innovation Corps; Lead; Life; Mediating; Medicine; Metabolic; Mission; Mus; Names; New Jersey; Organ; Patients; Peer Review; Phase; Prognosis; Publishing; Research; Role; Small Business Innovation Research Grant; Technology; Time; Tissues; Urticaria; arm; carbonate dehydratase; design; disabling symptom; drug discovery; inhibitor; mast cell; mastocytosis; member; mouse model; new therapeutic target; novel; novel therapeutics; pharmacologic; prevent; programs; reduce symptoms; response; stem cells

Executive Summary of Predicate SBIR Phase I Grant and Team The overall objective of our predicate SBIR Phase I grant, which started in June 2022, is to develop novel and potent compounds for treating mastocytosis. Mastocytosis is a rare set of diseases, characterized by the increased presence of mast cells in various tissues and organs. Patients suffering from mastocytosis often have diverse triggers that promote the activation of mast cells and subsequently the onset of debilitating symptoms, ranging from hives and abdominal pain to organ damage and life-threatening anaphylaxis. Although treatment options for mastocytosis patients exist, they are non-specific and are often limited to symptom alleviation and fail to adequately address the incapacitating and life-threatening prognoses mastocytosis patients face. Therefore, better therapies are urgently needed and NemaGen’s mission is to address this substantial need. Our cutting-edge technologies have, for the first time, identified a unique mast cell progenitor that is defined by its expression of the enzyme Carbonic anhydrase 1 (Car1). Carbonic anhydrases are a family of metabolic enzymes, known for their important roles in regulating pH and CO2 homeostasis. However, their role in mast cell development was unappreciated. NemaGen’s peer-reviewed and published findings have demonstrated that pharmacologically or genetically targeting Car1 is sufficient to prevent murine and human mast cell development. Moreover, we have shown that Car1 inhibition is sufficient to prevent mast cell responses in murine models of mastocytosis. Collectively, our exciting findings suggest that Car1 represents a new therapeutic target to treat mastocytosis and other mast cell-mediated diseases. We have developed a highly efficient drug discovery program, which is being accelerated with the assistance of our SBIR Phase I grant funding and funding from the venture capital arm of the New Jersey Health Foundation (NJHF). Since receiving our Phase I SBIR funding, we have engaged a leading medicinal chemist consultant to complement NemaGen’s established expertise in carbonic anhydrase enzymes and mast cell biology. This has resulted in the development of multiple lead compounds with more than 100-fold higher potency than established Car1 inhibitors (Table. 1) helping us to further advance our Phase 1 Aims. Overall, the specific aims of the proposed Phase I research were to: (1) Design, synthesize and optimize novel carbonic anhydrase inhibitors. (2) Evaluate the effects of Car enzyme inhibitors on enzymatic function and mast cell development. Our proposed I-Corps team will include the following three members. Member Names Role Nick Shubin, PhD NemaGen CEO Scott Alpizar, PhD Industry Expert, Venture Capitalist Jianya Peng, PhD PD/PI All three members are highly motivated and committed to the time requirements of the program.

谓词SBIR I期赠款和团队的执行摘要 始于2022年6月的谓词SBIR I期赠款的总体目标是开发新颖 以及治疗肥大症的潜在化合物。肥大症是一组罕见的疾病，其特征是 肥大细胞在各种组织和器官中的存在增加。患者肥大细胞增多症 通常具有多种触发因素，可促进肥大细胞的激活，然后开始 衰弱的症状，从蜂箱和腹痛到器官损伤和威胁生命 尽管存在肥大细胞增多症患者的治疗选择，但它们是非特异性的，并且是 通常仅限于减轻症状，无法充分解决丧失能力和生命的能力 预后肥大性患者面临。因此，迫切需要更好的疗法，而Nemagen的疗法 使命是满足这一巨大需求。 我们的尖端技术首次确定了一个独特的肥大细胞祖细胞 由酶碳酸酐酶1（CAR1）的表达定义。碳赤霉素是 代谢酶，以其在调节pH和二氧化碳稳态中的重要作用而闻名。但是，他们 在肥大细胞发育中的作用没有批准。 Nemagen的同行评审和发表的发现有 证明药理学或遗传靶向CAR1足以防止鼠和 人肥大细胞的发育。此外，我们已经表明CAR1抑制足以防止桅杆 肥大细胞增多鼠模型中的细胞反应。总的来说，我们令人兴奋的发现表明CAR1 代表了治疗肥大症和其他肥大细胞介导的疾病的新治疗靶标。 我们已经开发了一种高效的药物 发现计划正在加速 在我们的SBIR阶段I授予的协助下 风险投资部门的资金和资金 新泽西州健康基金会（NJHF） 自从我们获得I期SBIR资金以来，我们有 参与领先的医学化学顾问 完成Nemagen既定的专业知识 在碳酸酐酶和肥大细胞生物学中。这导致了多种铅化合物的发展，高100倍以上 效力比已建立的CAR1抑制剂（表1）帮助我们进一步促进了我们的第一阶段目标。 总体而言，拟议的I期研究的具体目的是： （1）设计，合成和优化新型的碳酸酐酶抑制剂。 （2）评估CAR酶抑制剂对酶促功能和肥大细胞发育的影响。 我们提议的I-Corps团队将包括以下三名成员。 会员名称角色 Nick Shubin，博士Nemagen首席执行官 斯科特·阿尔皮扎尔（Scott Alpizar）博士 行业专家，冒险 资本家 Jianya Peng，博士PD/PI 这三个成员都有积极进取，并致力于该计划的时间要求。