Resistance to Farnesyl Transferase inhibitors

描述（由申请人提供）：法尼基转移酶抑制剂（FTIs）是重要的抗癌化合物，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，由于药物靶点的点突变，可能会发生耐药性。本研究的目的是研究法尼基转移酶（FTase）点突变引起对FTI SCH66336/Lonafarnib耐药的能力。具体来说，将使用两种策略：a)随机诱变分析，其中将筛选突变的FTase库以筛选耐药性；b)位点定向诱变FTase活性位点的残基，这些残基是与酶结合的药物共晶中鉴定的关键药物结合接触。这样做是为了确保在随机诱变分析中没有发现的所有关键残基的分析。我们将进行广泛的分子建模，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。鉴定产生耐药性的突变有助于设计下一代治疗方法和鉴定患者的突变。因此，对这些突变进行彻底的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.