Resistance to Farnesyl Transferase inhibitors

对法尼基转移酶抑制剂的耐药性

• 批准号: 6932352
• 负责人: TAL RAZ
• 金额: $ 5.15万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-02 至 2007-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932352
• 关键词: active sites; alkyltransferase; antineoplastics; cell proliferation; chemical models; clinical research; drug resistance; enzyme activity; enzyme inhibitors; genetic mapping; human subject; laboratory mouse; point mutation; postdoctoral investigator; site directed mutagenesis

DESCRIPTION (provided by applicant): Farnesyl transferase inhibitors (FTIs) are important anticancer compounds, which are being widely tested for a variety of cancers. They have proven effective against leukemia in phase I/II clinical trials. Experience gained from another target specific drug - STI571/Gleevec indicates that drug resistance is likely to occur due to point mutations in the drug's target. The aim of this proposal is to investigate the ability of point mutations in farnesyl transferase (FTase) to cause resistance to the FTI SCH66336/Lonafarnib. Specifically, two strategies will be used: a.) random mutagenesis analysis in which a mutated library of FTase will be screened for drug resistance, and b.) site directed mutagenesis of residues in the active site of FTase which are critical drug-binding contacts identified in the co-crystal of the drug bound to enzyme. This will be done to insure the analysis of all critical residues, which were not discovered in the random mutagenesis analysis. We will perform extensive molecular modeling to map the mutations found onto FTase crystal structure to gain insight into the causes of drug resistance. The identification of resistance conferring mutations can help in the design of next generation therapy and in the identification of mutations in patients. A thorough evaluation of these mutations is, thus, critical for the evaluation of this drug.

描述（由申请人提供）：Farnesyl转移酶抑制剂（FTI）是重要的抗癌化合物，正在广泛测试各种癌症。 在I/II期临床试验中，它们已被证明有效抵抗白血病。 从另一种靶标的药物中获得的经验-STI571/gleevec表明，由于药物靶标的点突变，可能会发生耐药性。 该提案的目的是研究Farnesyl转移酶（FTase）中点突变对FTI SCH666336/LONAFARNIB引起抗性的能力。 具体而言，将使用两种策略：a。）随机诱变分析，其中将筛选出突变的FTase库中的耐药性和b。）位点，将FTase活性位点中残基的诱变定向诱变，这是在药物与酶结合的药物结合的共晶中确定的关键药物结合接触。 这将是为了确保对所有关键残基的分析，这在随机诱变分析中未发现。 我们将执行广泛的分子建模，以将发现的突变映射到FTase晶体结构上，以深入了解耐药性的原因。 抗抗性赋予突变的鉴定可以帮助设计下一代疗法和患者突变的鉴定。 因此，对这些突变的彻底评估对于评估该药物至关重要。