Chemoprotectants for Head-Neck Therapeutics

描述(由申请人提供)：头颈部治疗的化学保护剂口腔粘膜炎是化疗、放射治疗或化疗/放射联合治疗的主要剂量限制和复杂副作用。它被认为是头颈部癌症治疗中最重要的并发症。口腔粘膜炎伴随着巨大的疼痛，并可能导致危及生命的并发症。喉癌治疗后吞咽功能障碍尤其会使人虚弱。化学保护剂的开发是这项提议的中心目标。在初步研究中，反应生物公司发现了选择性、可逆的小分子caspase抑制剂，与临床试验中的化合物相比，它们具有多种优势。例如，许多制药公司的药物发现计划中的半胱氨酸酶抑制剂具有以下特征之一：不可逆性、多肽模拟性、泛型半胱氨酸酶抑制剂。在第一阶段的研究中，这些化合物在基于细胞的分析中非常活跃，在化学和辐射诱导的正常细胞系中显示了显著的细胞死亡预防活性。在这一第二阶段的应用中，我们将继续在基于细胞的分析和DMPK图谱中改进这些抑制剂的效力和疗效，以寻找动物模型试验中的最终领先者(S)。在这个新的提案中，主要目的是：1)结构-活性关系(SAR)研究，以提高caspase抑制剂的效力；2)结合化疗和放射治疗，确定caspase抑制剂的体外治疗条件；3)在三维口腔黏膜模型中测试caspase抑制剂的组织渗透性和对放射治疗口腔粘膜细胞的保护作用。 公共卫生相关性：头颈部治疗的化学保护剂口腔粘膜炎是化疗、放射治疗或联合化疗/放射治疗的主要剂量限制和复杂副作用。它被认为是头颈部癌症治疗中最重要的并发症。口腔粘膜炎伴随着巨大的疼痛，并可能导致危及生命的并发症。喉癌治疗后吞咽功能障碍尤其会使人虚弱。尽管细胞凋亡被认为是口腔粘膜炎的中心主题，但到目前为止，针对caspase抑制剂的研究还很少。反应生物学公司已经发现了一些新的、有效的和选择性的caspase抑制剂，并希望在化疗和辐射诱导的细胞凋亡检测中评估它们的细胞死亡保护活性。更多的SAR研究将提高这些化合物的效力，3D口腔粘膜模型的研究将进一步揭示caspase抑制剂的组织渗透和细胞保护特性，而不需要在体内动物模型中进行测试，这将有助于在早期消除有毒和无效的化合物，并减少未来在动物模型中的研究数量。

DESCRIPTION (provided by applicant): Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. The development of chemoprotectants is the central goal of this proposal. In preliminary studies, Reaction Biology Corporation has discovered selective, reversible, small molecule caspase inhibitors, which have multiple advantages compared to the compounds in the clinical trials. For example, caspase inhibitors from many pharmaceutical companies' drug discovery programs have one of more of the following characteristics: irreversible, peptide-mimic, Pan-caspase inhibitor. In Phase I studies, these compounds are very active in cell based assays, demonstrated significant cell death prevention activities in chemical and radiation induced cell death in normal cell lines. In this Phase II application, we will continue to improve these inhibitors in potency and efficacy in cell based assays and DMPK profiles, to look for the final lead(s) in animal model tests. In this new proposal, the key aims are: 1) Structure-Activity Relationship (SAR) studies to improve caspase inhibitors' potency; 2) Define caspase inhibitors' treatment conditions in vitro in conjugation with chemotherapy and radiation treatments; 3) Test caspase inhibitors' tissue penetration and efficacy in protecting oral mucous cells from radiation therapy in 3D oral mucosa model. PUBLIC HEALTH RELEVANCE: Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. Even though apoptosis is considered the central theme in oral mucositis, little work with caspase inhibitors has been conducted to date. Reaction Biology Corp. has discovered a few novel, potent and selective caspase inhibitors and would like to evaluate their cell death protection activities in chemotherapy and radiation induced apoptosis assays. Additional SAR studies will improve the potency of these compounds, and studies in 3D oral mucosa models will further reveal tissue penetration and cell protective properties of caspase inhibitors without testing in vivo animal model, which will help to eliminate toxic and ineffective compounds in early stage, and reducing the number of studies in animal models in the future.