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: 7943004
• 负责人: MARCIE A GLICKSMAN
• 金额: $ 25.59万
• 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/7943004
• 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)：具有坏死形态特征的受调控的细胞死亡途径最近已成为重要的基本生物学过程。这些通路在人类疾病中的相关性，例如急性神经损伤，开始被认识到。识别可用作探查关键生物靶标作用的小有机分子，对于从机制上理解受调控的坏死细胞死亡途径和制定治疗人类疾病的策略至关重要。在过去的几年里，我们描述了一条受调控的坏死性细胞死亡途径(称为坏死性下垂)，确定了该途径中的一个关键分子靶点(RIP1激酶)，并报道了四种不同的针对RIP1激酶的小分子抑制剂。其中三个系列直接抑制RIP1激酶的活性，而其中一个系列间接抑制该途径。最近我们发现了一种新的间接抑制物(NEC-10)。初步数据表明，这种间接抑制物的作用机制可能是通过抑制RIP1泛素化，这已被证明是RIP1信号转导的关键。这项建议的主要目标是优化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泛素化在调节坏死性细胞死亡中的作用。 与公共健康相关：细胞通常被认为通过两个过程死亡，称为凋亡(一个受调节的过程)和坏死(一个非调节的过程)。虽然坏死机制普遍存在于许多神经系统疾病中，如中风和创伤性脑损伤，但由于认为它不能调节，因此一直没有成为治疗的靶点。然而，我们和其他人发现，在某些情况下，这不是真的，如果更好地了解细胞死亡的分子机制，可能会开发出针对细胞死亡的坏死形式的治疗方法。我们建议开发小的有机化合物，可以用作分子探针来研究坏死，这样就可以设计治疗策略来治疗这种形式的细胞死亡存在的神经系统疾病。