Conferring in vivo metabolic resistance to a highly selective anti-AML agent

赋予高选择性抗 AML 药物体内代谢抗性

• 批准号: 8687089
• 负责人: Edward J Merino
• 金额: $ 20.99万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687089
• 关键词: Acute Myelocytic Leukemia; Address; Albumins; Animal Model; Antineoplastic Agents; Antioxidants; Biochemical; Blood; CD34 gene; Cell Death; Cells; Chemicals; Clinical; Collaborations; Cytarabine; DNA; DNA lesion; Data; Disease; Doctor of Philosophy; Doxorubicin; Drug Design; Drug Kinetics; Evaluation; FLT3 gene; Genotype; Goals; Growth; Half-Life; Hematopoietic Neoplasms; Hour; Human; Hydrolysis; In Vitro; Injection of therapeutic agent; Laboratories; Lead; Liver Microsomes; Longevity; Malignant Neoplasms; Measurement; Metabolic; Metabolism; Modeling; Molecular; Mus; Outcome; Patients; Pediatric Hospitals; Pharmaceutical Chemistry; Phase; Phenotype; Plasma; Positioning Attribute; Prodrugs; Property; Public Health; Reaction; Reactive Oxygen Species; Relapse; Research; Resistance; Route; Signal Transduction; Stem cells; Superoxides; Survival Rate; Testing; Therapeutic; Transducers; Translating; Translations; Work; analog; angiogenesis; base; cancer cell; cell transformation; clinically relevant; combat; cytotoxic; design; drug discovery; forging; high reward; improved; in vivo; leukemia; mouse model; novel; outcome forecast; pre-clinical; public health relevance; ras Oncogene; receptor; research study; standard of care; stem

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a blood cancer with the poorest prognosis at approximately 20%. Thus, novel anticancer agents to combat this disease are needed. This proposal uses a pro-drug strategy to design anticancer agents where an AML-cell specific phenotype is harnessed to activate the agent. It is known that AML cancer cells possess elevated reactive oxygen species. Reactive oxygen species benefit cancer cells by enhancing angiogenesis and activating growth cascades. This proposal seeks to translate these biochemical findings into useful anticancer agents. The long-term goal of the project is to design novel molecular entities for use as AML anti-cancer agents. The overall objective of this application, which is the next step toward attainment of our long-term goal, is to identify a soluble and general metabolism-resistant agent capable of eradicating AML cancer cells in vivo. The hypothesis is that agents protected at a key position will degrade with a half-life of 4-5 hours allowing in vivo AML cell eradication. The hypothesis has been formulated based on preliminary data that demonstrates ROS-specific activation, verifies the precise DNA lesion formed by these pro-drugs, a promising increase in AML-mouse survival, and PK measurements. To accomplish the goals, an interdisciplinary team of a chemical biologist (to synthesize and biochemically evaluate agents) and a cancer biologist (to characterize the anticancer potential of the agents in vivo) has been forged. The testing of the central hypothesis will occur through one aim. (1) Identify an in vivo selective agent with appropriate pharmacokinetic properties. In this proposal strategic placement of specific groups on the lead agent will occur. The novel functionalities impart resistance to metabolic phase 1 and 2 reactions as well as albumin sequestration. These functionalities slowly hydrolyze to give sustained concentrations of the lead compound in vivo. In vitro, quantification of hydrolysis (enzymatic and intrinsic), plasma stability, metabolic degradation by liver microsomes, and activation. These properties will be quantified as t1/2, Vmax and Km. In vivo examination of agent half-life and concentration-dependent AML cell death via FACS. The outcomes of the aims are as follows. First, identifying an agent with a strong pharmacokinetics (PK) profile will show that ROS-agents can survive in vivo and that these new designs are potentially clinically relevant anti-cancer agents with good therapeutic windows. Second, showing in vivo AML cell death will be an important and exciting outcome since it will positively position the team to achieve the longer-term goal of in vivo efficacy. Positive results will show a new molecular entity with a nove mechanism of action that can be used to improve prognosis in AML and potentially other cancers. This proposal is expected to serve as the basis for a subsequent R01 submission that will analyze continued medicinal chemistry efforts, ADME, fully evaluate efficacy, and establish the biochemical mechanism of the agents to complete pre-clinical experiments.

描述（由申请人提供）：急性髓样白血病（AML）是一种血液癌，预后最差，约为20％。因此，需要新颖的抗癌剂来对抗这种疾病。该提案采用亲毒品策略来设计抗癌药，其中利用AML细胞特异性表型来激活该药物。众所周知，AML癌细胞具有升高的活性氧。活性氧通过增强血管生成和激活生长级联反应使癌细胞受益。该建议旨在将这些生化发现转化为有用的抗癌药。该项目的长期目标是设计新型分子实体，以用作AML抗癌剂。该应用的总体目标是实现我们的长期目标的下一步，是确定能够在体内消除AML癌细胞的可溶性和一般代谢的剂。假设是，在关键位置受保护的试剂将以4-5小时的半衰期降解，从而使体内AML细胞消除。该假设是基于初步数据提出的，该数据证明了ROS特异性激活，验证了这些促毒物形成的精确DNA病变，有希望的AML小鼠存活率和PK测量值有望增加。为了实现目标，化学生物学家的跨学科团队（合成和生化评估剂）和癌症生物学家（以体内代理的抗癌潜力来表征）。中央假设的检验将通过一个目标进行。 （1）确定具有适当药代动力学特性的体内选择剂。在此提案中，将发生特定组在铅代理上的战略放置。新型功能对代谢1和2反应以及白蛋白隔离赋予了抗性。这些功能缓慢地水解以在体内产生持续浓度的铅化合物。体外，水解定量（酶促和内在），血浆稳定性，肝微粒体的代谢降解和激活。这些特性将被量化为T1/2，VMAX和KM。通过FACS对药剂的半衰期和浓度依赖性AML细胞死亡的体内检查。目标的结果如下。首先，识别具有强药代动力学（PK）剖面的药物将表明ROS-Agent可以在体内生存，并且这些新设计可能是具有良好治疗窗口的临床上相关的抗癌药物。其次，显示体内AML细胞死亡将是一个重要而令人兴奋的结果，因为它将积极地定位团队以实现体内疗效的长期目标。积极的结果将显示出具有尖锐作用机理的新分子实体，可用于改善AML和其他潜在癌症的预后。预计该提案将作为随后的R01提交的基础，该提交将分析持续的药物化学工作，ADME，充分评估疗效，并建立代理的生化机制以完成临床前实验。