Discovery and Target Identification of Senolytic Agents

项目摘要/摘要 衰老细胞(SCs)已成为治疗衰老和老年性疾病的潜在靶点。 感觉剂是一种可以选择性杀死干细胞的小分子，有可能被开发为“抗肿瘤药物”。 老龄化“药物可通过以下方式延长人类的健康寿命(无残疾或其他损伤的寿命) 预防或治疗与年龄有关的疾病。最近，我们报道了ABT-263(Navitoclax)的发现。 通过筛选合理选择的化合物的文库，有效和选择性地使用感光剂。我们的 研究表明，ABT-263在亚致死状态下具有恢复造血干细胞(HSCs)的功能 辐射(6Gy)和自然衰老的小鼠通过耗尽干细胞，包括衰老的HSCs，从而证明 感觉剂的治疗潜力。按照同样的方法，我们鉴定出了第二种感觉剂 胡椒素(PL)是一种从各种胡椒(辣椒)品种中分离出来的天然饮食产品。不像 ABT-263通过抑制Bcl2蛋白诱导SC细胞凋亡，其潜在的分子机制 PL在诱导SC死亡中的作用(MMOA)尚未确定，增加了发现新分子的可能性 抗衰老药物开发的靶点。因此，我们假设PL可以作为一个有希望的线索 新型感受器裂解剂的开发，并可用于识别对 SC生存。本申请的目标是发现和评估PL类似物(“风笛”)作为 有效的和选择性的感光剂，确定它们的分子靶标，并阐明这些新的MMOA 探员们。这些目标将通过实现以下具体目标来实现：1)设计， 合成和评价新型风笛剂，以提高PL的感光活性；2)鉴定和验证 在干细胞中的蛋白质靶点，并阐明其MMOA；以及3)体内疗效评价 首席风笛手。这些拟议目标的成功不仅将生产基于PL的抗衰老药物 开发候选，还识别和验证新的分子靶标(S)，以使未来的设计和 基于目标的新型感觉剂的发现和对细胞生物学的更多洞察力 衰老与光合作用和胡萝卜的MMOA。

PROJECT SUMMARY/ABSTRACT Senescent cells (SCs) have emerged as a potential therapeutic target for aging and age-related diseases. Senolytic agents, small molecules that can selectively kill SCs, have the potential to be developed as “anti- aging” drugs that can extend human healthspan (years of life without disability or other impairment) by preventing or treating age-related diseases. Recently, we reported the discovery of ABT-263 (navitoclax) as a potent and selective senolytic agent through screening of a library of rationally selected compounds. Our studies show that ABT-263 functionally rejuvenates hematopoietic stem cells (HSCs) in both sublethally irradiated (6 Gy) and naturally aged mice by depleting SCs, including senescent HSCs, thus demonstrating the therapeutic potential of senolytic agents. Following the same approach, we have identified a second senolytic agent, piperlongumine (PL), a natural dietary product isolated from a variety of Piper (pepper) species. Unlike ABT-263, which induces SC apoptosis by inhibiting Bcl-2 proteins, the underlying molecular mechanisms of action (MMOA) of PL in inducing SC death are undefined, raising the potential of discovering novel molecular targets for senolytic drug development. Therefore, we hypothesize that PL can serve as a promising lead for the development of novel senolytic agents and can be used to identify molecular targets that are important for SC survival. The objectives of this application are to discover and evaluate PL analogues (“piperlogues”) as potent and selective senolytic agents, identify their molecular targets, and elucidate the MMOA of these novel agents. These objectives will be accomplished by carrying out the following specific aims: 1) design, synthesize and evaluate novel piperlogues to improve the senolytic activity of PL; 2) identify and validate the protein targets of PL and piperlogues in SCs, and elucidate their MMOA; and 3) evaluate the in vivo efficacy of lead piperlogues. Success in these proposed aims will not only produce PL-based anti-aging drug development candidates but also identify and validate novel molecular target(s) to enable future design and target-based discovery of novel senolytic agents and to gain more insights into the biology of cellular senescence and the MMOA of PL and piperlogues.