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Anti-cancer implications of small molecule compounds targeting proliferating cell nuclear antigen.

机译：靶向增殖细胞核抗原的小分子化合物的抗癌作用。

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摘要

Cancer is a persistent global health concern despite advancements in prevention, detection, and treatment. Acquired chemotherapy resistance and dose-limiting toxicities continue to plague current cancer treatment modalities, indicating a desperate need for new and improved molecularly targeted anti-cancer therapies. Proliferating cell nuclear antigen (PCNA) is a non-oncogenic mediator of DNA replication. For this reason, PCNA function is essential to the uncontrolled proliferation of cancer cells. PCNA is highly expressed in tumors, determining it as a reliable marker of proliferation and a potentially desirable target for cancer therapy.;Functional PCNA is a ring-shaped homotrimer which is loaded onto chromatin by replication factor C (RFC). PCNA plays a crucial role in DNA replication by providing replicative DNA polymerases the high processivity required to duplicate the entire genome. Furthermore, PCNA functions as a scaffold protein, binding a multitude of protein partners involved in many vital cellular processes such as DNA replication, DNA repair, and cell cycle control. Collectively, these many functions of PCNA and its localization at the replisome put PCNA in a central position for determining the fate of the replication fork.;The homotrimeric structure of PCNA is crucial for its function. Therefore, we performed an in silico screen of a drug-like chemical library for small molecule compounds that would bind the monomer-monomer interface of PCNA in attempts to identify compounds that would alter homotrimer stability. The PCNA-inhibitors (PCNA-Is) identified were found to bind PCNA homotrimers with a high affinity and promote homotrimer stabilization by serving as a "linker" at the monomer-monomer interface. This increased stability resulted in a decrease in PCNA chromatin-association in various tumor cell lines. Treatment with PCNA-Is inhibited DNA replication and growth of tumor cells. Additional studies using PCNA-I1, the most potent of the PCNA-Is identified, were carried out to determine the downstream effects of targeting PCNA in two prostate cancer cell lines which differed in mutational status. Treatment with PCNA-I1 resulted in an accumulation of DNA double-strand breaks and induced programmed cell death of PC-3 and LNCaP cells. Moreover, PCNA-I1 sensitized LNCaP prostate cancer cells to cisplatin treatment. However, regardless the molecular drivers, mutational status, or mechanism of programmed cell death, short treatment with PCNA-I1 was cytotoxic to prostate cancer cells. These findings were mirrored in vivo, as intravenous administration of PCNA-I1 inhibited tumor growth and induced apoptosis in a xenograft model of prostate cancer. Furthermore, PCNA-I1 treatment showed no evidence of systemic toxicity at the administered dose.;Structure-activity relationship (SAR) analysis of 46 compounds led to the identification of two compounds with superior potency and improved solubility to PCNA-I1. These compounds stabilized PCNA homotrimers and reduced PCNA chromatin-association, confirming the mechanism of action for this class of compounds. Future studies will focus on further characterizing the downstream effects of PCNA-Is and their potential usefulness as both a monotherapy and combination therapy for the treatment of cancer.
机译：尽管在预防，检测和治疗方面取得了进步，但是癌症仍是全球性的健康问题。获得性化疗耐药性和剂量限制性毒性继续困扰着当前的癌症治疗方式，这表明迫切需要新的和改进的分子靶向抗癌疗法。增殖细胞核抗原（PCNA）是DNA复制的非致癌介质。因此，PCNA功能对于癌细胞不受控制的增殖至关重要。 PCNA在肿瘤中高表达，将其确定为增殖的可靠标志物和癌症治疗的潜在理想靶标。功能性PCNA是一种环状同型三聚体，通过复制因子C（RFC）加载到染色质上。 PCNA通过提供复制性DNA聚合酶提供复制整个基因组所需的高生产力，在DNA复制中起着至关重要的作用。此外，PCNA充当支架蛋白，与参与许多重要细胞过程（例如DNA复制，DNA修复和细胞周期控制）的多种蛋白伴侣结合。总的来说，PCNA的许多功能及其在复制体中的定位将PCNA置于决定复制叉命运的中心位置。PCNA的同源三聚体结构对其功能至关重要。因此，我们对类似药物的化学文库进行了计算机模拟筛选，以筛选可与PCNA的单体-单体界面结合的小分子化合物，从而尝试鉴定可改变同三聚体稳定性的化合物。发现已鉴定的PCNA抑制剂（PCNA-Is）以高亲和力结合PCNA同三聚体，并通过在单体-单体界面处充当“接头”来促进同三聚体稳定。这种增加的稳定性导致各种肿瘤细胞系中PCNA染色质缔合的减少。 PCNA-Is的治疗抑制了肿瘤细胞的DNA复制和生长。使用PCNA-I（已鉴定出的最有力的PCNA-I）进行了其他研究，以确定在突变状态不同的两种前列腺癌细胞系中靶向PCNA的下游效应。用PCNA-I1处理导致DNA双链断裂的积累，并诱导PC-3和LNCaP细胞的程序性细胞死亡。此外，PCNA-I1使LNCaP前列腺癌细胞对顺铂治疗敏感。然而，无论分子驱动因素，突变状态或程序性细胞死亡的机制如何，用PCNA-1短期治疗对前列腺癌细胞具有细胞毒性。这些发现在体内得到了反映，因为在前列腺癌的异种移植模型中静脉内给予PCNA-I1可抑制肿瘤生长并诱导细胞凋亡。此外，PCNA-I1处理在给药剂量下没有显示系统毒性的证据。;对46种化合物的结构-活性关系（SAR）分析导致鉴定出两种具有更强效用和对PCNA-I1改善的溶解性的化合物。这些化合物稳定了PCNA均三聚体并降低了PCNA染色质的缔合，证实了这类化合物的作用机理。未来的研究将集中于进一步表征PCNA-Is的下游效应及其作为单一疗法和联合疗法治疗癌症的潜在用途。

著录项

  • 作者

    Dillehay McKillip, Kelsey L.;

  • 作者单位

    University of Cincinnati.;

  • 授予单位 University of Cincinnati.;
  • 学科 Oncology.;Molecular biology.;Pharmaceutical sciences.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 160 p.
  • 总页数 160
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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