Pharmacogenetics of Nucleobase and Nucleoside Analog Drugs

摘要 合成的核碱基和核苷类似物（NNA）代表一类重要的治疗剂， 多种适应症，其中41种NNA药物获得美国食品和药物管理局（FDA）批准， 抗癌和/或抗病毒治疗。然而，大多数NNA药物都有严重的不良反应， 可能危及生命，并且其药理学作用在患者间存在广泛的差异。因此有 迫切需要了解NNA药物毒性和反应差异的生物学基础， 开发更安全、更有效地使用这类重要药物的方法。 为了应对这些挑战，我们在过去5年中的NIGMS资助工作集中在药物遗传学方面， 硫嘌呤，一种广泛用于治疗白血病和自身免疫性疾病的NNA药物。我们发现了基因 一种新的药物代谢基因NUDT 15的变异体与巯嘌呤治疗期间的严重骨髓抑制相关 治疗儿童白血病，阐明了NUDT 15调节 硫嘌呤细胞毒性，系统地鉴定了NUDT 15中的药物遗传学变体，也导致了 开发NUDT 15指导的硫嘌呤给药的临床指南。最近，我们发现了两个反- 病毒药物，即阿昔洛韦和更昔洛韦，作为NUDT 15的新底物，表明NUDT 15可以 混杂地代谢各种NNA药物。事实上，NUDT 15属于人类NUDIX的一大类。 使天然的或化学修饰的核苷酸去磷酸化的酶。 基于这些发现，我假设NUDIX酶（包括NUDT 15）可能是重要的 NNA药物的代谢酶，主要通过调节核苷酸药物代谢物的去磷酸化。 为此，我计划合理扩展我的研究计划，广泛研究NNA药物的药物遗传学， 总体目标是确定NNA药物反应的新型药物遗传学标志物，然后 利用这些信息开发遗传学指导的个体化治疗方法。在下一次融资中 周期，我将在两个独特但相关的方向进行研究：1）识别NUDT 15变异相关 与更昔洛韦药物灭活，并开发NUDT 15基因型指导的方法， 2）广泛检查人类NUDIX酶在NNA药物活性中的作用， 14种FDA批准的抗癌药物 鉴于临床上使用的NNA药物数量众多，迫切需要更安全地使用NNA药物， 有效地，我的研究计划解决了一个重大的科学挑战，是实质性的范围， 适合长期追求。我相信，在下一个供资周期， 继续支持NIGMS。

Abstract Synthetic nucleobase and nucleoside analogs (NNA) represent an important class of therapeutic agents with a variety range of indications, with 41 NNA drugs approved by the US Food and Drug Administration (FDA) for anti-cancer and/or anti-viral therapy. However, most NNA drugs are associated severe adverse effects that can be life-threatening, and there is a wide inter-patient variability in their pharmacologic effects. Therefore, there is a pressing need to understand the biological basis of the variance in NNA drug toxicity and response, to develop ways to more safely and more effectively use this important class of drugs. To address these challenges, our NIGMS-funded work in the past 5 years focused on pharmacogenetics of thiopurines, an NNA drug widely used to treat leukemia and autoimmune diseases. We discovered genetic variants in a novel drug metabolism gene NUDT15 associated with severe myelosuppression during thiopurine treatment in children with leukemia, elucidated the pharmacological mechanism by which NUDT15 modulates thiopurine cytotoxicity, systematically identified pharmacogenetic variants in NUDT15, and also led the development of clinical guides for NUDT15-guided thiopurine dosing. More recently, we have identified two anti- viral drugs, namely acyclovir and ganciclovir, as novel substrates of NUDT15, indicating that NUDT15 can promiscuously metabolize a variety of NNA drugs. In fact, NUDT15 belongs to a large class of human NUDIX enzymes that dephosphorylate native or chemically modified nucleotides. Based on these findings, I hypothesize that NUDIX enzymes (including NUDT15) are potentially important metabolizing enzymes for NNA drugs, primarily by regulating dephosphorylation of nucleotide drug metabolite. To this end, I plan to rationally expand my research program to study pharmacogenetics of NNA drugs broadly, with the overarching objectives to identify novel pharmacogenetic markers for NNA drug response and then use this information to develop approaches for genetics-guided treatment individualization. In the next funding cycle, I will pursue research in two distinctive but related directions: 1) to identify NUDT15 variants associated with ganciclovir drug inactivation and develop NUDT15 genotype-guided approaches to individualize anti-viral therapy, and 2) to broadly examine human NUDIX enzymes for their role in the activity of NNA drugs, focusing on 14 FDA-approved anti-cancer agents. Given the large number of NNA drugs used clinically and the pressing need to use NNA drugs more safely and effectively, my research program addresses a significant scientific challenge and is substantive in scope and appropriate for long-term pursuit. I am confident that sustained progress in the next funding cycle is likely with continuation of the NIGMS support.