Pharmacogenomics and the drug discovery pipeline - When should it be implemented?
Pharmacogenomics and the drug discovery pipeline - When should it be implemented?
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DOI：
10.2165/00129785-200505010-00005
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发表时间：
2005-01-01
期刊：
影响因子：
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通讯作者：
McHale, D
中科院分区：
文献类型：
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作者：
Penny, MA;McHale, D
开发改良药物的关键因素之一在于了解我们治疗的复杂疾病的分子基础，利用基于连锁不平衡的全基因组关联策略的进展调查与疾病的遗传关联将为治疗提供新的靶点，并确定相关的通路。发病机理遗传学研究结合基因表达、蛋白质组学和代谢组学分析为识别疾病的分子亚型提供了有力的工具。使用这些分子数据，药物基因组学有可能在管道的许多阶段影响药物发现和开发过程，有助于靶点识别和增加对治疗原理的信心。这通过5-脂氧合酶激活蛋白（ALOX 5AP/FLAP）与心肌梗死风险增加以及趋化因子受体5（CCR 5）与HIV感染和治疗的确定关联来举例说明。药物基因组学已被用于肿瘤学，以证明分子数据有助于评估疾病异质性，从而鉴定对药物如甲磺酸伊马替尼的反应的分子标记（Gleevec（R））和曲妥珠单抗（赫赛汀（R））靶基因变异的知识允许通过适当设计临床前研究和使用相关的遗传学方法来早期评估多态性的临床意义。动物模型药物开发临床前阶段的重点药物基因组学策略将产生数据，为化合物的探索性和全面开发提供药物基因组学计划。批准后的机会显示了大型特征良好的数据集对于系统评估遗传决定因素对药物不良反应和疗效的贡献的价值。大型IV期试验中基因组样本的可用性也为进一步了解疾病异质性的分子基础提供了宝贵的资源，为下一代改进药物的靶点鉴定和验证提供了反馈到药物发现过程中的数据。
One of the key factors in developing improved medicines lies in understanding the molecular basis of the complex diseases we treat. Investigation of genetic associations with disease utilizing advances in linkage disequilibrium-based whole genome association strategies will provide novel targets for therapy and define relevant pathways contributing to. disease pathogenesis. Genetic studies in conjunction with gene expression, proteomic, and metabonomic analyses provide a powerful tool to identify molecular subtypes of disease. Using these molecular data, pharmacogenomics has the potential to impact on the drug discovery and development process at many stages of the pipeline, contributing to both target identification and increased confidence in the therapeutic rationale. This is exemplified by the identified association of 5-lipoxygenase-activating protein (ALOX5AP/FLAP) with increased risk of myocardial infarction, and of the chemokine receptor 5 (CCR5) with HIV infection and therapy. Pharmacogenomics has already been used in oncology to demonstrate that molecular data facilitates assessment of disease heterogeneity, and thus identification of molecular markers of response to drugs such as imatinib mesylate (Gleevec (R)) and trastuzumab (Herceptin (R)).Knowledge of genetic variation in a target allows early assessment of the clinical significance of polymorphism through the appropriate design of preclinical studies and use of relevant animal models. A focussed pharmacogenomic strategy at the preclinical phase of drug development will produce data to inform the pharmacogenomic plan for exploratory and full development of compounds. Opportunities post-approval show the value of large well-characterized data sets for a systematic assessment of the contribution of genetic determinants to adverse drug reactions and efficacy. The availability of genomic samples in large phase IV trials also provides a valuable resource for further understanding the molecular basis of disease heterogeneity, providing data that feeds back into the drug discovery process in target identification and validation for the next generation of improved medicines.