Small molecule probes for elucidating necrotic cell death mechanisms

用于阐明坏死细胞死亡机制的小分子探针

• 批准号: 8286520
• 负责人: Gregory D Cuny
• 金额: $ 10.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286520
• 关键词: Acute; Affinity; Apoptosis; Belief; Biochemical; Biological; Biological Process; Cell Death; Cell Survival; Cells; Cellular Assay; Characteristics; Data; Goals; Human; In Vitro; Jurkat Cells; Mediating; Modeling; Molecular; Molecular Probes; Molecular Target; Morphology; Necrosis; Nervous System Trauma; Neurons; Pathway interactions; Phase; Phosphotransferases; Physiology; Process; Proteins; Reagent; Recombinants; Reporter; Reporting; Retrieval; Role; Series; Signal Transduction; Stroke; Structure-Activity Relationship; Therapeutic; Traumatic Brain Injury; Ubiquitination; analog; base; design; human disease; inhibitor/antagonist; nervous system disorder; novel; public health relevance; small molecule; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Regulated cell death pathways with morphological characteristics of necrosis have recently emerged as important fundamental biological processes. The relevance of these pathways in human diseases, e.g. acute neurological injuries, is beginning to be appreciated. Identification of small organic molecules that can be used as probes to interrogate the roles of key biological targets are crucial for achieving a mechanistic understanding of regulated necrotic cell death pathways and for formulating therapeutic strategies for treating human diseases. Over the past several years we have described a regulated necrotic cell death pathway (termed necroptosis), identified a key molecular target (RIP1 kinase) in the pathway and reported on four distinct series of small molecule inhibitors that target RIP1 kinase. Three of these series inhibit RIP1 kinase activity directly, while one of these series inhibits the pathway indirectly. Recently we have identified a new indirect inhibitor (Nec-10). Preliminary data suggests that the mechanism of action for this indirect inhibitor may be through inhibiting RIP1 ubiquitination, which has been shown to be critical for RIP1 signaling. The primary goal of this proposal is to optimize Nec-10 for potency, to design and synthesize mechanistic probes based on Nec-10 analogs and to utilize these compounds for elucidating the role of RIP1 ubiquitination in regulated necrotic cell death. PUBLIC HEALTH RELEVANCE: Cells are generally thought to die through two processes, called apoptosis (a regulated process) and necrosis (a non-regulated process). Although the necrosis mechanism is prevalent in many neurological diseases, such as stroke and traumatic brain injury, it has not been targeted by therapies due to the belief that it can not be modulated. However, we and others have found that in some cases this is not true and that therapeutics could potentially be developed for the necrosis form of cell death if its molecular mechanism was better understood. We propose to develop small organic compounds that can be used as molecular probes to investigate necrosis so that therapeutic strategies can be devised for the treatment of neurological diseases where this form of cell death is present.

描述（由申请人提供）：最近出现的具有坏死形态特征的受调节细胞死亡途径已成为重要的基本生物学过程。这些途径在人类疾病中的相关性，例如急性神经损伤开始受到赞赏。可以用作探索关键生物学靶标的探针的小有机分子的鉴定对于实现对受调节的坏死细胞死亡途径的机械理解和制定治疗人类疾病的治疗策略至关重要。在过去的几年中，我们描述了一个受调节的坏死细胞死亡途径（称为坏死性），鉴定出途径中的一个关键分子靶靶（RIP1激酶），并在四个不同的靶向RIP1激酶的小分子抑制剂上报告了。这些系列中的三个直接抑制RIP1激酶活性，而其中一个序列间接抑制了途径。最近，我们确定了一种新的间接抑制剂（NEC-10）。初步数据表明，这种间接抑制剂的作用机理可能是通过抑制RIP1泛素化的，这已被证明对RIP1信号传导至关重要。该提案的主要目标是优化NEC-10的效力，设计和合成基于NEC-10类似物的机械探针，并利用这些化合物来阐明RIP1泛素化在调节的坏死细胞死亡中的作用。 公共卫生相关性：通常认为细胞死于两个过程，称为细胞凋亡（一个受调节过程）和坏死（一个不受监管的过程）。尽管在许多神经系统疾病（例如中风和脑损伤）中，坏死机制普遍存在，但由于人们认为无法调节它，因此尚未受到疗法的靶向。但是，我们和其他人发现，在某些情况下，这是不正确的，如果更好地理解细胞死亡的坏死形式，则可以为坏死形式开发治疗剂。我们建议开发小有机化合物，这些化合物可以用作分子探针研究坏死，以便可以设计治疗策略来治疗存在这种细胞死亡形式的神经系统疾病。