Developing novel therapeutics for the treatment of mastocytosis

谓词SBIR第一阶段授权和团队的执行摘要 我们于2022年6月开始的谓词SBIR第一阶段拨款的总体目标是开发新的 以及治疗肥大细胞增多症的有效化合物。肥大细胞增多症是一种罕见的疾病，其特征是 肥大细胞在各种组织和器官中的增多。患有肥大细胞增多症的患者 通常有不同的触发因素，促进肥大细胞的激活，并随后发生 虚弱的症状，从麻疹和腹痛到器官损伤和生命危险 过敏反应。虽然肥大细胞增多症患者有治疗选择，但这些治疗方法是非特异性的，而且 往往仅限于缓解症状，未能充分解决使人丧失能力和危及生命的问题 肥大细胞增多症患者面临的预后。因此，迫切需要更好的治疗方法和NemaGen的 其使命是满足这一实质性需求。 我们的尖端技术首次确定了一种独特的肥大细胞前体细胞 由其表达的碳酸脱氢酶1(Car1)定义。碳酸氢酶是一类 代谢酶，以其在调节pH和二氧化碳动态平衡方面的重要作用而闻名。然而，他们的 在肥大细胞发育中的作用没有得到重视。NemaGen的同行评议和发表的研究结果 证明以Car1为靶点在药理上或基因上足以预防小鼠和 人类肥大细胞发育。此外，我们已经证明抑制car1足以预防肥大。 肥大细胞增多症小鼠模型的细胞反应。总而言之，我们令人兴奋的发现表明，Car1 代表了治疗肥大细胞增多症和其他肥大细胞介导性疾病的新的治疗靶点。 我们已经开发出一种高效的药物 发现计划，该计划正在加速 在我们SBIR第一期赠款的帮助下 资金和来自风险投资部门的资金 新泽西健康基金会(NJHF)的。 自收到第一阶段SBIR资金以来，我们已经 聘请了一位顶尖的药物化学家顾问 以补充NemaGen的成熟专业知识 碳酸酐酶和肥大细胞生物学。这导致了多种先导化合物的发展，这些化合物的含量要高出100倍以上 比现有的Car1抑制剂更有效(表。1)帮助我们进一步推进第一阶段目标。 总的来说，拟议的第一阶段研究的具体目标是： (1)新型碳酸酐酶抑制剂的设计、合成和优化。 (2)评价CAR酶抑制剂对肥大细胞发育和酶功能的影响。 我们提议的i-Corps团队将包括以下三名成员。 成员名称角色 尼克·舒宾，NemaGen博士首席执行官 斯科特·阿尔皮萨，博士 风险投资行业专家 资本家 彭建亚，博士，PD/PI 所有三名成员都非常有动力，并致力于计划的时间要求。

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.