Pharmacogenetics of Nucleobase and Nucleoside Analog Drugs

摘要 合成核碱基和核苷类似物 (NNA) 是一类重要的治疗药物，具有以下特点： 适应症范围广泛，有41种NNA药物获得美国食品和药物管理局（FDA）批准用于 抗癌和/或抗病毒治疗。然而，大多数 NNA 药物都会产生严重的副作用， 危及生命，并且其药理作用存在很大的患者间差异。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、更有效地使用这一类重要药物的方法。 为了应对这些挑战，我们在过去 5 年中由 NIGMS 资助的工作重点是药物遗传学 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。我们发现遗传 新型药物代谢基因 NUDT15 的变异与硫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 NUDT15 调节的药理学机制 硫嘌呤细胞毒性，系统地鉴定了 NUDT15 中的药物遗传学变异，并且还领导了 制定 NUDT15 指导的硫嘌呤给药临床指南。最近，我们发现了两种反 病毒药物，即阿昔洛韦和更昔洛韦，作为NUDT15的新底物，表明NUDT15可以 混杂代谢多种 NNA 药物。事实上，NUDT15属于人类NUDIX的一大类 使天然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 NUDT15）具有潜在的重要性 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 药物反应的新药物遗传学标记，然后 利用这些信息来开发遗传学指导的个体化治疗方法。在接下来的融资中 周期中，我将在两个独特但相关的方向进行研究：1）识别相关的 NUDT15 变体 更昔洛韦药物灭活并开发 NUDT15 基因型引导的个体化抗病毒方法 疗法，2) 广泛检查人类 NUDIX 酶在 NNA 药物活性中的作用，重点关注 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、更安全地使用NNA药物 我的研究计划有效地解决了重大的科学挑战，并且在范围和范围上具有实质性 适合长期追求。我相信下一个融资周期可能会取得持续进展 继续 NIGMS 支持。

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.