Isoxazole Small Molecules That Induce Stem Cell Differentiation

描述(申请人提供)：在美国，大约每6例死亡中就有1例是由于心脏病导致的心脏病发作(心肌梗塞，MI)。在心脏病发作中幸存下来的患者心脏受到永久性损害，死亡风险更高。干细胞疗法为心脏修复和再生提供了一种新的工具，最终可以增进健康，延长生命，并减轻心肌梗死后患者的疾病和残疾负担。这项建议旨在开展化学和生物学交界处的研究，长期目标是识别具有诱导成人心脏内源性干细胞群体走向心肌梗死后心脏修复能力的类药物分子。通过广泛的研究，已经确定了一种能够阻止心肌梗死后瘢痕组织(纤维化)形成和心肌再生的铅分子。这项建议的目标是扩大小分子文库，以鉴定新的具有更高效力的先导化合物，并利用它们合成探针，以确定生物靶点，并寻求关于干细胞分化的性质和行为的基础知识。这反过来将为使用更合理的方法开发具有更多类似药物特性的分子奠定基础和基本的生物学理解。为了实现这一目标，我们提出了以下目标：(1)设计、合成和评估当前铅分子的类似物(2)评估生物学数据，并从铅分子中合成光标记或放射性标记的探针，以确认生物靶点并帮助理解干细胞分化所涉及的生物学过程和机制。铝分子的合成将使用文献中报道的交叉偶联化学，并由我们实验室开发。生物活性将通过荧光素酶报告基因检测进行评估。

DESCRIPTION (provided by applicant): About 1 in every 6 deaths in the United States is due to heart disease resulting in heart attack (myocardial infraction, MI). Patients who survive a heart attack suffer permanent damage to the heart and carry a higher risk of mortality. Stem cell based therapies provide a new tool towards cardiac repair and regeneration that can ultimately enhance health, lengthen life, and reduce the burdens of illness and disability for patients post MI. This proposal is geared towards conducting research at the interface of chemistry and biology with the long term objective to identify drug-like molecules with the ability to induce an endogenous population of stem cells in the adult heart toward cardiac repair post MI. Through extensive research, a lead molecule able to deter the formation of scar tissue (fibrosis) and regenerate heart muscle post MI has been identified. The goal of this proposal is to expand the small molecule library to identify new lead compounds with increased potency and utilize them in synthesizing probes to confirm the biological target as well as seek fundamental knowledge about the nature and behavior of stem cell differentiation. This will in turn set the foundation and basic biological understanding to develop molecules with more drug like characteristics using a more rational approach. To accomplish this goal the following aims are proposed: (1) Design, synthesize, and evaluate analogues of our current lead molecule (2) Evaluate biological data and synthesize photolabeled or radiolabeled probes from lead molecules that can confirm the biological target and assist in the understanding of biological processes and mechanisms involved in stem cell differentiation. Al molecules will be synthesized using cross coupling chemistry reported in the literature and developed in our laboratory. The biological activity will be evaluated through luciferase reporter gene assays.