Developing novel therapeutics for the treatment of mastocytosis

摘要 肥大细胞增多症是一个术语，用于描述一组罕见的疾病，其特征是肥大细胞增多， 肥大细胞在各种组织和器官中的发育和增强的存在。一旦启动，桅杆 细胞通过其大量产生组胺、白三烯、三尖杉酯碱和 许多其他效应分子，促进瘙痒，燃烧，平滑肌收缩和危及生命 过敏反应，所有这些都是肥大细胞增多症的常见症状。虽然患者患有 肥大细胞增多症的处方抗组胺药和肥大细胞稳定剂，治疗选择有限， 这种疾病的严重形式极难治疗，并且仍然危及生命。此外，不完整的 对调节肥大细胞发育的因素的理解极大地限制了 设计选择性靶向肥大细胞的新疗法。NemaGen的已发表和初步研究 已经揭示了碳酸酐酶（Car）1仅由肥大细胞祖细胞表达。 此外，我们已经证明，小分子介导的Car1抑制足以防止小鼠 和人类肥大细胞的发育。此外，我们的数据表明，在体内治疗与已知的 碳酸酐酶抑制剂足以防止鼠肥大细胞发育和炎症 肥大细胞增多症模型。总的来说，这些研究表明，Car1代表了一种新的治疗靶点， 肥大细胞增多症和肥大细胞介导的炎症的治疗。虽然现有的碳酸酐酶 抑制剂是可用的，我们的研究表明，其有效剂量远远超过所需的 翻译应用。为了解决这个问题，我们已经建立了一个强大的团队和有效的工作流程， 我们来合成和测试新的Car酶抑制剂。此外，我们的数据表明，我们可以生成 比目前可用的抑制剂更有效。这些令人兴奋的发现构成了 本SBIR建议的基础和两个具体目标：（i）设计，合成和优化新的碳 脱水酶抑制剂。(ii)评价Car酶抑制剂对酶功能和肥大细胞的影响 在体外和体内的发展。总的来说，这些临床前研究将使我们能够产生新的汽车 用于治疗肥大细胞增多症和其它肥大细胞相关病症的酶抑制剂。

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.