Development of Zinc Metallochaperones as Mutant p53 Targeted Anti-cancer Drugs

锌金属伴侣作为突变 p53 靶向抗癌药物的开发

• 批准号: 9005386
• 负责人: Darren Richard Carpizo
• 金额: $ 37.99万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005386
• 关键词: Affinity; Alleles; Amino Acids; Antineoplastic Agents; Apoptotic; Area; Binding; Biology; Biophysics; Cancer Patient; Cells; Chelating Agents; Clinic; Clinical; Complementary DNA; Complex; DNA; DNA Binding Domain; Data; Defect; Development; Dose; Drug Design; Drug Targeting; Feedback; Foundations; Frequencies; Genes; Genetic; Goals; Homeostasis; Hour; Human; In Vitro; Ionophores; Ions; Knowledge; Laboratories; Lead; Malignant Neoplasms; Measures; Mediating; Metalloproteins; Metals; Missense Mutation; Molecular Conformation; Mutate; Mutation; Outcome; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Post-Translational Protein Processing; Protein p53; Proteins; Public Health; Reactive Oxygen Species; Regulator Genes; Research; Research Personnel; Roentgen Rays; Specificity; Structure; TP53 gene; Therapeutic; Toxic effect; Validation; Zinc; Zinc deficiency; base; cancer cell; cancer type; design; drug development; functional restoration; in vivo; killings; member; monomer; mouse model; mutant; neoplastic cell; novel; novel therapeutics; programs; public health relevance; research study; restoration; small molecule; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Researchers have acknowledged for decades that the small-molecule restoration of wild type p53 function in tumors is one of the ultimate, yet elusive goals in cancer drug development. TP53 is the most commonly mutated gene in cancer and loss of its function is one of the central drivers of tumorigenesis. The majority of mutations are missense and generate a defective protein found at high levels in cancer cells. The p53-R175H is the most common missense mutant and is misfolded because the substitution impairs the protein's ability to bind zinc. We discovered a zinc chelating small-molecule (ZMC1) that can restore wild type structure/function to the p53-R175H by restoring zinc-binding and facilitating proper folding (so-called zinc metallochaperone (ZMC) mechanism). ZMC1 "reactivates" mutant p53 and selectively kills cancer cells by a p53 mediated apoptotic program both in vitro and in vivo. The pharmacologic restoration of a folding defect in a metalloprotein by metal ion delivery is unprecedented in drug development. We found that other zinc chelators with a similar affinity (Kd) for zinc can function as ZMCs and ZMCs can reactivate other mutants with impaired zinc-binding. Therefore, we hypothesize that ZMCs can be developed as effective mutant p53 targeted anti-cancer drugs. This will be investigated through the following specific aims: 1) Determine the impact of zinc homeostatic mechanisms on ZMC1 pharmacodynamics. Cells respond to the ZMC1 surge in zinc levels by normalizing zinc through homeostatic mechanisms. We hypothesize that these mechanisms regulate ZMC1 activity. We will explore this through mechanistic studies that measure the effect on ZMC1 activity of manipulating zinc regulatory genes in tumors cells. 2) Define the p53 mis-sense mutational spectrum that is amenable to ZMC reactivation. ZMC1 is proposed to reactivate the mutant class with impaired zinc binding; however the full spectrum of this class is unknown. We hypothesize that the mutants closest to the zinc-binding pocket are most likely to have impaired zinc binding. We will study the 15 most frequent mutants within 10Å of the zinc-binding pocket. This will define the potential patient poo for ZMCs. 3) Design a ZMC optimized for potency, toxicity, and efficacy in vivo. We have designed novel chemotypes that have ZMC activity and are more potent than ZMC1 in vitro. We will validate these results in vivo. Our team is composed of three laboratories that are leading this area of research. Their expertise is the following: 1) p53 biology (Darren Carpizo), Zinc/p53 folding biophysics (Stewart Loh), and zinc chelator drug design (David Augeri). Relevance to public health: The research performed in this proposal will provide the foundation for the development of a new class of anti-cancer drugs that target the most commonly mutated gene in human cancer. These drugs will have broad activity against all types of cancers.

 描述（由适用提供）：研究人员已经承认，数十年来，肿瘤中野生型p53功能的小分子恢复是癌症药物开发中的最终但弹性目标之一。 TP53是癌症中最常见的突变基因，其功能丧失是肿瘤发生的核心驱动因素之一。大多数突变是错义的，并在癌细胞中产生高水平的蛋白质缺陷。 p53-R175H是最常见的错义突变体，被误折，因为替代损害了蛋白质结合锌的能力。我们发现了一个锌螯合的小分子（ZMC1），该分子可以通过恢复锌结合并支撑适当的折叠（所谓的锌金属伴侣（ZMC）机制）来恢复野生型结构/功能。 ZMC1“重新激活”突变体p53，并通过p53介导的凋亡程序在体外和体内有选择地杀死癌细胞。金属离子递送中金属蛋白中折叠缺陷的药理恢复在药物开发中是前所未有的。我们发现，其他具有相似亲和力（KD）的锌螯合剂可以用作ZMC和ZMC可以用锌结合受损的其他突变体重新激活其他突变体。因此，我们假设可以开发ZMC作为有效的突变体p53靶向抗癌药。这将通过以下特定目的进行研究：1）确定锌稳态机制对ZMC1药效学的影响。细胞通过稳态机制使锌归一化锌水平的ZMC1激增。我们将通过机械研究来探讨这一点，以衡量肿瘤细胞中操纵锌调节基因的ZMC1活性的影响。 2）定义适合ZMC重新激活的p53误差突变光谱。提议ZMC1用受损的锌结合重新激活突变类别。但是，这类的全部范围尚不清楚。我们假设最接近锌结合口袋的突变体最有可能受损锌结合。我们将研究锌结合口袋10的最常突变体。这将定义ZMC的潜在患者便便。 3）设计用于在体内效力，毒性和效率的ZMC。我们设计了具有ZMC活性的新型化学型，并且在体外比ZMC1更有潜力。我们将在体内验证这些结果。我们的团队由三个领导这一研究领域的实验室组成。他们的专业知识如下：1）P53生物学（Darren Carpizo），锌/p53折叠生物物理学（Stewart Loh）和锌螯合剂药物设计（David Augeri）。与公共卫生有关：在该提案中进行的研究将为开发一种新型的抗癌药物的基础，该药物针对人类癌症中最常见的基因。这些药物将对所有类型的癌症具有广泛的活性。