Resistance to Farnesyl Transferase inhibitors

描述(申请人提供)：法尼基转移酶抑制剂(FTI)是一种重要的抗癌化合物，目前正被广泛用于各种癌症的测试。在I/II期临床试验中，它们已被证明对白血病有效。从另一种靶向特异性药物STI571/Gleevec获得的经验表明，由于药物靶点的突变，可能会发生耐药性。这项建议的目的是研究法尼基转移酶(FTase)点突变导致对FTI SCH66336/Lonafarnib耐药的能力。具体而言，将使用两种战略：a.随机突变分析，其中突变的FTase文库将被筛选抗药性，以及b.)定点突变FTase活性部位的残基，这些残基是在药物与酶结合的共晶中确定的关键药物结合接触。这样做是为了确保所有关键残基的分析，这些残基在随机突变分析中没有发现。我们将进行广泛的分子模拟，将发现的突变映射到FTase晶体结构上，以深入了解耐药的原因。耐药突变的鉴定有助于下一代疗法的设计和患者突变的鉴定。因此，对这些突变的彻底评估对于该药物的评估至关重要。

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.