Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic
Evolution of Poly(ADP-ribose) Polymerase-1 (PARP-1) Inhibitors. From Concept to Clinic
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DOI：
10.1021/jm100012m
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发表时间：
2010-06-24
影响因子：
7.3
通讯作者：
Ferraris, Dana V.
中科院分区：
文献类型：
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作者：
Ferraris, Dana V.
近 3 年来，聚 (ADP-核糖) 聚合酶-1 (PARP-1a) 一直是人们积极追求的药物发现靶标。这种丰富的核酶通常被称为“DNA 的守护天使”1，已成为 20 多个药物化学项目的焦点，涉及中风、心肌缺血、癌症、炎症和糖尿病等广泛的治疗领域（图 1）。 2 尽管该靶点具有巨大的治疗潜力，并且学术界和工业界为此付出了巨大的努力，但 PARP-1 抑制剂直到最近才在临床试验中取得进展。几种 PARP-1 抑制剂在癌症治疗 II 期临床试验中的最新结果引起了国家媒体的关注。 3 在 PARP-1 抑制剂的几种潜在治疗适应症中，最有希望的两个主要领域是缺血和癌症。本综述旨在向读者简要总结 PARP-1 作为治疗靶点的基本原理，解释 PARP-1 抑制剂药效团，并提供 PARP-1 药物发现计划的最新进展。本视角将提供关键 PARP-1 出版物的历史记录，这些出版物在 20 世纪 80 年代末和 1990 年代初逐渐引起了生物制药行业的兴趣。此外，我将讨论为什么 PARP-1 在 1990 年代末和 2000 年代初受到如此多的关注，而如今的药物化学研究却略有下降（图 1）。主要的 PARP-1 药物化学项目将重点关注先导化合物生成、先导化合物优化、候选药物选择和临床进展。 PARP-1 生物学功能的许多方面不属于本药物化学综述的范围。因此，读者应参考以下引文来回顾 PARP 酶家族，4-6 聚（ADP-核糖）的生物学功能，5 PARP-1 和细胞内信号传导，7 PARP 和 DNA 修复，8 PARP 和表观遗传学，9PARP 和血管生成，10 以及 PARP-1 在炎症中的作用。 11, 12 关于这一主题的药物化学 30 年也提供了一些优秀的药物化学评论，其中大部分早于临床候选结构和最近的临床试验结果的披露。 13-17日
Poly (ADP-ribose) polymerase-1 (PARP-1a) has been an actively pursued drug discovery target for almost 3 decades. Often referred to as the “guardian angel of DNA”, 1 this abundant nuclear enzyme has been the focus of over 20 medicinal chemistry programs in a wide range of therapeutic areas encompassing stroke, cardiac ischemia, cancer, inflammation, and diabetes (Figure 1). 2 Despite the great therapeutic potential for this target and the tremendous academic and industrial efforts dedicated to it, only recently have PARP-1 inhibitors made headway in clinical trials. Recent results from several PARP-1 inhibitors in phase II clinical trials for cancer therapy have attracted the attention of national media. 3 Of the several potential therapeutic indications for PARP-1 inhibitors, the two major areas that hold the most promise are ischemia and cancer. This review is structured to provide the readers with a brief summary of the rationale for PARP-1 as a therapeutic target, to explain the PARP-1 inhibitor pharmacophore, and to provide an update on the progress of the PARP-1 drug discovery programs. This Perspective will offer a historical account of the critical PARP-1 publications that instilled the interest of the biopharmaceutical industry in the late 1980s and early 1990s. Furthermore, I will discuss why PARP-1 received so much attention in the late 1990s and early 2000s followed by the slight decline in the medicinal chemistry efforts today (Figure 1). The major PARP-1 medicinal chemistry programs will be highlighted focusing on the lead generation, lead optimization, candidate selection, and clinical progress. Many aspects of the biological functions of PARP-1 fall outside the scope of this medicinal chemistry review. For this reason, the reader should refer to the following citations for a review of the PARP family of enzymes, 4-6 the biological functions of poly (ADP-ribose), 5 PARP-1 and intracellular signaling, 7 PARP and DNA repair, 8 PARP and epigenetics, 9PARP and angiogenesis, 10 and the role of PARP-1 in inflammation. 11, 12 The 30 years of medicinal chemistry on this topic have also afforded some excellent medicinal chemistry reviews, most of which predated the disclosure of clinical candidate structures and recent clinical trial results. 13-17