Translesion synthesis inhibitors as a new class of cancer chemotherapeutics.
Translesion synthesis inhibitors as a new class of cancer chemotherapeutics.
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DOI：
10.1080/13543784.2021.1850692
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发表时间：
2021-01
影响因子：
6.1
通讯作者：
Hadden MK
中科院分区：
文献类型：
--
作者：
Patel SM;Dash RC;Hadden MK
跨损伤合成(TLS)是一种DNA损伤耐受机制，它用一种专门的、低保真的TLS DNA聚合酶取代复制的DNA聚合酶，这种聚合酶可以在活跃复制过程中复制过去的DNA损伤。最近的研究表明，TLS在复制一线基因毒剂诱导的过去DNA损伤中发挥了主要作用，导致疗效下降和获得性化疗耐药。考虑到这一点，靶向TLS作为一种与一线基因毒性药物相结合的策略已成为开发新型抗癌佐剂的一种有前途的方法。在这篇综述中，我们简要介绍了TLS及其在癌症中的作用。我们还讨论了针对TLS机制中的各种TLS DNA聚合酶或关键的蛋白质-蛋白质相互作用(PPI)的抑制剂的鉴定和开发。TLS抑制剂已经显示出初步的前景；然而，他们的继续研究对于更充分地了解这一新兴类别的抗癌化疗药物的临床潜力是必不可少的。重要的是要确定TLS中涉及的特定蛋白质是否是最佳靶点。此外，扩大对当前遗传毒性化疗与TLS抑制剂协同作用的理解将指导设计联合治疗的临床策略。
Translesion synthesis (TLS) is a DNA damage tolerance mechanism that replaces the replicative DNA polymerase with a specialized, low-fidelity TLS DNA polymerase that can copy past DNA lesions during active replication. Recent studies have demonstrated a primary role for TLS in replicating past DNA lesions induced by first-line genotoxic agents, resulting in decreased efficacy and acquired chemoresistance. With this in mind, targeting TLS as a combination strategy with first-line genotoxic agents has emerged as a promising approach to develop a new class of anti-cancer adjuvant agents. In this review, we provide a brief background on TLS and its role in cancer. We also discuss the identification and development of inhibitors that target various TLS DNA polymerases or key protein-protein interactions (PPIs) in the TLS machinery. TLS inhibitors have demonstrated initial promise; however, their continued study is essential to more fully understand the clinical potential of this emerging class of anti-cancer chemotherapeutics. It will be important to determine whether a specific protein involved in TLS is an optimal target. In addition, an expanded understanding of what current genotoxic chemotherapies synergize with TLS inhibitors will guide the clinical strategies for devising combination therapies.
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16
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影响因子：
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