DNA甲基转移酶抑制剂的研究进展

DNA甲基化是调控基因表达的一种重要的表观遗传学过程,在基因组稳定性和癌症发生方面起着重要作用.DNA甲基转移酶抑制剂可通过抑制DNA异常甲基化的发生,进而激活沉默的抑癌基因来防治癌症.本文从作用机制的角度,介绍DNA甲基转移酶抑制剂近年来的研究进展.     

DNA methyltransferase inhibitors in cancer: a chemical and therapeutic patent overview and selected clinical studies

Introduction: DNA methylation is an epigenetic modification that modulates gene expression without altering the DNA base sequence. It plays a crucial role in cancer by silencing tumor suppressor genes (TSG). The DNA methyltransferases (DNMT) are the enzymes that catalyze DNA methylation and they are interesting therapeutical targets since DNA methylation is reversible such that an aberrant hypermethylation of DNA can be reverted by inhibition of DNMTs. Today, two drugs are on the market for the treatment of myelodysplastic syndrome, azacitidine and decitabine.

Areas covered: Here, we present a review of the patents describing the chemistry and biological activities of novel DNMT inhibitors and discuss select clinical studies.

Expert opinion: DNMT inhibitors have shown efficacy in clinics. However, highly efficient and specific DNMT inhibitors have not yet been identified. Improving methods will certainly lead to the prediction of novel directly binding inhibitors in the future.     

脱氧核糖核酸甲基化抑制剂的研究进展

近年来,越来越多的研究发现异常的DNA甲基化和肿瘤、自身免疫性疾病、衰老等密切相关。由于DNA甲基化状态是可以改变的,故利用DNA甲基化抑制剂达到防治肿瘤的目的成为可能。本文综述了DNA甲基化抑制剂的种类、作用机制及临床研究的新进展,探讨了其抗肿瘤治疗推广到临床应用的可行性。     

Exploiting the therapeutic potential of the PI3K-AKT-mTOR pathway in enriched populations of gynecologic malignancies

Given the prevalence of phosphatase & tensin homolog mutations in histologic specimens harvested from patients with endometrial cancer, significant interest in systemic treatment with PI3K/Akt/mTOR inhibitors has emerged. Several Phase II trials have been completed studying mTOR inhibitors in advanced/recurrent endometrial cancer. The mTOR pathway also appears to be important in some cervical cancers. Finally, because clear cell carcinoma of the ovary and renal cell carcinoma have a shared histology, the potential for activity of mTOR inhibitors in clear cell cancer of the ovary is implicit. This article reviews the results of Phase II clinical trials of PI3K/Akt/mTOR pathway inhibitors in patients with endometrial cancer, and discusses the potential therapeutic landscape of mTOR inhibition in enriched populations in gynecologic cancers.     

DNA methyltransferase inhibitors: an updated patent review (2012-2015)

Introduction: DNA methyltransferases (DNMTs), important enzymes involved in epigenetic regulation of gene expression, represent promising targets in cancer therapy. DNMT inhibitors (DNMTi), which can modulate the aberrant DNA methylation pattern in a reversible way via inhibiting DNMT activity, have attracted significant attention in recent years.

Areas covered: This review outlines the newly patented inhibitors targeting DNMTs, mainly incorporating small molecular inhibitors and oligonucleotide derivatives. The chemical structures, biological activity, and the encouraging clinical research in progress are delineated in detail.

Expert opinion: Two drugs, azacitidine and decitabine, have evidently shown efficacy in hematologic malignancies, yet do not work well on solid tumors, have low specificity, substantial toxicity, and poor bioavailability. With the rapid advancement in systems biology, drug combinations, such as DNMTi, in conjugation with histone deacetylase inhibitors (HDACi) or immunotherapy, probably serve as an efficient way of implementing epigenetic therapy. Meanwhile, the resolved autoinhibitory structures of DNMTs afford a novel strategy for targeting the protein-protein interface involved in the autoinhi-bitory interactions. The molecular mechanism underlying the conformational transitions would also shed new light on the design of allosteric inhibitors. Both strategies would produce inhibitors with more selectivity compared to nucleotide derivatives.     

TGF-β: friend or foe? The role of TGF-β/SMAD signaling in epigenetic silencing of ovarian cancer and its implication in epigenetic therapy

Importance of the field: The TGF-β signaling pathway plays an important role in regulating numerous cellular processes including growth inhibition of ovarian surface epithelial (OSE) cells. However, epithelial ovarian cancer is refractory to the inhibitory functions of TGF-β, and yet TGF-β induces metastasis or epithelial–mesenchymal transition (EMT) in advanced ovarian cancer. How TGF-β plays a certain role in one cell but a different role in its malignant counterpart is not fully understood.

Areas covered in this review: The role of TGF-β/SMAD signaling both in normal OSE cells and ovarian cancer as well as how dysregulation of this signaling pathway leads to epigenetic silencing of its downstream targets in ovarian neoplasias are reviewed. The therapeutic implication of this signaling pathway in epigenetic therapy of ovarian cancer are also discussed.

What the reader will gain: The reader will gain insight on how dysregulation of TGF-β signaling alters promoter methylation and histone modifications of TGF-β downstream targets in ovarian cancer.

Take home message: Disruption of TGF-β/SMAD signaling leads to epigenetic silencing of its target genes transiently through histone modifications but permanently by promoter hypermethylation. Targeting the TGF-β signaling pathway may be a novel therapeutic strategy in ovarian cancer.     

长链非编码RNAPVT1在妇科癌症中的研究进展

长链非编码RNA(Long non-coding RNAs,LncRNAs)在多种癌症的发生发展中发挥着关键作用.LncRNA PVT1在妇科恶性肿瘤中的重要性引起了人们的广泛关注,主要反映在癌细胞的病理过程和肿瘤的临床进展以及预后方面.本文主要围绕LncRNA PVT1在妇科恶性肿瘤中的表达及调控作用进行综述.探讨L...     

Poly-ADP-ribose polymerases (PARPs) as a therapeutic target in the treatment of selected cancers

ABSTRACT

Introduction: The implementation of poly-ADP-ribose polymerase (PARP) inhibitors for therapy has created potential treatments for a wide spectrum of malignancies involving DNA damage repair gene abnormalities. PARPs are a group of enzymes that are responsible for detecting and repairing DNA damage and therefore play a key role in maintaining cell function and integrity. PARP inhibitors are drugs that target DNA repair deficiencies. Inhibiting PARP activity in cancer cells causes cell death.

Areas covered: This review summarizes the role of PARP inhibitors in the treatment of cancer. We performed a systematic literature search in February 2019 in the electronic databases PubMed and EMBASE. Our search terms were the following: PARP, PARP inhibitors, PARPi, Poly ADP ribose polymerase, cancer treatment. We discuss PARP inhibitors currently being investigated in cancer clinical trials, their safety profiles, clinical resistance, combined therapeutic approaches and future challenges.

Expert Opinion: The future could bring novel PARP inhibitors with greater DNA trapping potential, better safety profiles and improved combined therapies involving hormonal, chemo-, radio- or immunotherapies. Progress may afford wider indications for PARP inhibitors in the treatment of cancer and the utilization for cancer prevention in high-risk mutation carriers. Research efforts should focus on identifying novel drugs that target DNA repair deficiencies.     

Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis

Abstract

DNA methylation plays an intricate role in the regulation of gene expression and events that compromise the integrity of the methylome may potentially contribute to disease development. DNA methylation is a reversible and regulatory modification that elicits a cascade of events leading to chromatin condensation and gene silencing. In general, normal cells are characterized by gene-specific hypomethylation and global hypermethylation, while cancer cells portray a reverse profile to this norm. The unique methylome displayed in cancer cells is induced after exposure to carcinogenic metals such as nickel, arsenic, cadmium, and chromium (VI). These metals alter the DNA methylation profile by provoking both hyper- and hypo-methylation events. The metal-stimulated deviations to the methylome are possible mechanisms for metal-induced carcinogenesis and may provide potential biomarkers for cancer detection. Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance.     

Alterations in S-adenosylhomocysteine metabolism decrease O6-methylguanine DNA methyltransferase gene expression without affecting promoter methylation

The DNA repair enzyme O⁶-methylguanine DNA methyltransferase (MGMT) protects cells against the cytotoxic effects of alkylating agents. Therefore, modulation of MGMT expression in tumors is a possible strategy for improving the efficiency of cancer therapy. MGMT expression and activity is lost frequently in association with DNA hypermethylation of the MGMT promoter region. Since DNA and mRNA methylation are controlled by intracellular S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) levels, we hypothesized a role for AdoMet/AdoHcy ratio in the regulation of MGMT promoter methylation and mRNA expression.

Our initial studies showed that AdoMet/AdoHcy ratios vary over a wide range (7.0–50) in different glioblastoma and hepatoma cell lines. The studied cell lines exhibit distinct MGMT promoter methylation patterns: MGMT promoter was completely unmethylated in LN-18 and Tu 132 cells, hypermethylated in LN-229, U87-MG, and Tu 113 cells, and partially methylated in HepG2 cells. Furthermore, MGMT promoter methylation patterns and global DNA methylation are not related to intracellular AdoMet/AdoHcy ratio under control conditions. To lower AdoMet/AdoHcy ratio to values <1 we used AdoHcy hydrolase inhibitor adenosine-2′,3′-dialdehyde (30 μM) and found that neither short-term (24 h) nor long-term changes (7 weeks) in AdoMet/AdoHcy ratio altered global or MGMT promoter methylation. However, experimentally elevated AdoHcy levels significantly decreased MGMT mRNA levels by >50% in all MGMT-expressing cell lines, which is most likely the result of impaired mRNA methylation. Thus, the present study suggests elevation of AdoHcy levels by AdoHcy hydrolase inhibition as a novel pharmacological approach to modulate MGMT expression and to increase the responsiveness to alkylating agents.     

Structure-based design,discovery and development of checkpoint kinase inhibitors as potential anticancer therapies

Psychiatric disorders have a heterogeneous biological basis, where environmental factors interplay with non-mendelian genetics to produce complex cognitive/behavioural syndromes such as schizophrenia. Recent findings indicate a proportion of schizophrenia is associated with genomic copy number variation, suggesting that alteration of gene expression levels rather than direct mutation may play a role. Epigenetic mechanisms could be the crucial link between external stimuli and gene expression, influencing schizophrenia risk. These are dynamic reversible systems that offer much promise as targets for future therapies.     

Activity landscape of DNA methyltransferase inhibitors bridges chemoinformatics with epigenetic drug discovery

Introduction: Activity landscapes are valuable tools for exploring systematically the structure–activity relationships (SAR) of chemical databases. Their application to analyze the SAR of DNA methyltransferase (DNMT) inhibitors, which are attractive compounds as potential epi-drugs or epi-probes, provides useful information to identify pharmacophoric regions and plan the development of predictive models and virtual screening.

Areas covered: This paper highlights different approaches for conducting SAR analysis of datasets with a particular focus on the activity landscape methodology. SAR information of DNMT inhibitors (DNMTi), stored in a public database, is surveyed to further illustrate concepts and generalities of activity landscape modeling with a special emphasis on structure–activity similarity (SAS) maps.

Expert opinion: The increasing SAR information reported for DNMTi opens up avenues to implement activity landscape methods. Despite several activity landscape methods, such as SAS maps, being well established, these need further refinement. For instance, novel combinations of multiple representations, such as the addition of Z-values of similarity (fusion-Z), lead to more robust representations of consensus SAS maps. Density SAS maps improve the visualization of the SAR. A survey of activity cliffs (i.e., pairs of compounds with high structural similarity but high differences in potency) of DNMTi available in a public database suggest that it is feasible to develop predictive models for non-nucleoside DNMTi using approaches such as quantitative structure-activity relationships and that non-nucleoside DNMTi in ChEMBL can be used as query molecules in similarity-based virtual screening.     

Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors

Introduction: For several decades’ cancer treatment targeting DNA repair pathways incorporated both chemo- and radiotherapy only. However, over the last decade improved knowledge of DNA repair processes has paved the way for the development of novel targeted drugs abrogating DNA repair signaling. Checkpoint kinase inhibitors are exciting molecules and hold promise in the treatment of both solid and hematologic malignancies. Herein, we discuss preclinical and clinical studies with this class of molecules.

Areas covered: In this review, we discuss the role of check point kinase 1 (CHK-1) in DNA repair and provide a comprehensive summary of pre-clinical and early phase clinical trials with CHK-1 inhibitors. We also provide molecular structural basis of CHK-1inhibitors binding to CHK-1.

Expert opinion: Available data from both pre-clinical and early clinical studies illustrates potential efficacy of this class of molecules when combined with antimetabolites in treating both solid and hematologic malignancies. In addition, there might be an additive role in combining this class of molecules to PARP inhibitors, platinum chemotherapy, or radiation therapy in p53 or BRCA mutated tumors. The safety of the aforementioned combination needs to be closely evaluated in the ongoing clinical trials.     

依维莫司在女性生殖器恶性肿瘤治疗中的应用

目的 总结依维莫司的药理作用,探讨其单独或联合治疗女性生殖器常见恶性肿瘤的效果,为晚期和复发转移的患者提供新的治疗思路。方法 检索PubMed、Medline、中国知网、万方数据库、维普数据库有关依维莫司治疗子宫颈癌、卵巢癌和子宫内膜癌的相关文献,并结合临床现状对其进行综述。结果 依维莫司能够通过多种途径阻碍肿瘤细胞的生长、代谢以及肿瘤新生血管形成等,起到抗肿瘤作用。尤其当依维莫司联合化疗、放疗、激素治疗和其他分子靶向药物时,有望克服肿瘤的耐药性,提高对肿瘤治疗的敏感性。结论 依维莫司在晚期和复发转移的女性生殖器恶性肿瘤治疗中前景可观,对于提高患者预后具有很大的潜力。     

AEZS-108: a targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors

Introduction: Receptors for the luteinizing hormone-releasing hormone [LHRH, also known as gonadotropin-releasing hormone (GnRH)] can be regarded as an ideal target for a personalized medicine approach in cancer therapy. LHRH receptors are expressed in about 80% of human endometrial and ovarian cancers, 86% of prostate cancer, and about 50% of breast cancers including triple-negative breast cancer, as well as bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas. Apart from the pituitary and reproductive organs, other organs and hematopoietic stem cells express LHRH receptors. Thus, a targeted cytotoxic LHRH analog such as AEZS-108 (formerly known as AN-152), in which doxorubin is linked to the LHRH agonist [D-Lys⁶]LHRH, appears to be a suitable drug for targeted chemotherapy of cancers expressing receptors for LHRH, which would be more efficacious and less toxic than standard systemic chemotherapy.

Areas covered: This review discusses the development of AEZS-108, its targeting mechanism, preclinical studies, and clinical trials in patients with endometrial, ovarian, prostatic, and bladder cancers. We emphasize its development as a personalized medicine approach. The studies reviewed demonstrate the effects of the cytotoxic LHRH analog, AEZS-108, mediated by LHRH receptors, in in vivo models of LHRH-receptor-positive human endometrial, ovarian, breast, prostatic, colorectal, pancreatic, and bladder cancers xenografted into nude mice. Intravenous administration of AEZS 108 inhibits the growth of LHRH-receptor-positive tumors better than equimolar doses of the cytotoxic agent doxorubicin and is far less toxic. AEZS 108 has no antitumor activity in cancers negative to LHRH receptor. This strongly supports the concept of targeting cytotoxic chemotherapy to tumor cells expressing LHRH receptors. Early clinical trials have demonstrated the efficacy of AEZS-108. A Phase I trial assessed the maximum tolerated dose and pharmacokinetics and pharmacodynamics of AEZS-108 given once every 3 weeks in patients with gynecological cancers. Two Phase II studies in heavily pretreated ovarian and recurrent endometrial cancers showed good clinical activity after a maximum of six courses of AEZS-108 as a single agent. Ongoing clinical studies with AEZS-108 in men with castration-resistant prostate cancer and patients with chemotherapy refractory bladder cancer had shown early signs of clinical efficacy. Side effects are moderate and easily manageable. In particular, no pituitary or cardiac toxicity is observed.

Expert opinion: AEZS-108 is a cytotoxic analog designed for receptor-mediated targeted chemotherapy and consists of an LHRH carrier linked to doxorubicin. Preclinical studies demonstrate that the uptake of AEZS-108 is achieved by receptor-mediated endocytosis. Results of Phase I and II clinical trials in patients with gynecological cancers demonstrated anticancer activity without cardiotoxicity even in highly pretreated patients. Phase I/II studies in castration-resistant prostate cancer and chemotherapy refractory bladder cancer are in progress. Targeted chemotherapy with a cytotoxic analog of LHRH, such as AEZS-108, is therefore being considered for Phase III studies in advanced endometrial cancers positive for LHRH receptor. LHRH receptors are also present in human colon cancers, melanomas, lymphomas, and sarcomas, and treatment of these cancers with AEZS-108 should also be undertaken. Before such treatment with AEZS-108 is begun, the status of tumoral LHRH receptors of patients must be determined.     

A patent review of arginine methyltransferase inhibitors (2010–2018)

Introduction: Protein arginine methyltransferases (PRMTs) are fundamental enzymes that specifically modify the arginine residues of versatile substrates in cells. The aberrant expression and abnormal enzymatic activity of PRMTs are associated with many human diseases, especially cancer. PRMTs are emerging as promising drug targets in both academia and industry.

Areas covered: This review summarizes the updated patented inhibitors targeting PRMTs from 2010 to 2018. The authors illustrate the chemical structures, molecular mechanism of action, pharmacological activities as well as the potential clinical application including combination therapy and biomarker-guided therapy. PRMT inhibitors in clinical trials are also highlighted. The authors provide a future perspective for further development of potent and selective PRMT inhibitors.

Expert opinion: Although a number of small molecule inhibitors of PRMTs with sufficient potency have been developed, the selectivity of most PRMT inhibitors remains to be improved. Hence, novel approaches such as allosteric regulation need to be further studied to identify PRMT inhibitors. So far, three PRMT inhibitors have entered clinical trials, including PRMT5 inhibitor GSK3326595 and JNJ-64619178 as well as PRMT1 inhibitor GSK3368715. PRMT inhibitors with novel mechanism of action and good drug-like properties may shed new light on drug research and development progress.     

Targeting epigenetic regulatory mechanisms in cancer chemoprevention

Dysregulation of the epigenome plays a fundamental role in tumour development. Epigenetic events are a major mechanism for inactivating tumour suppressor and DNA repair genes and occur ubiquitously during the early stages of tumour development. Unlike genes inactivated by mutation, genes silenced epigenetically are intact and potentially responsive to reactivation by small molecules. This review discusses the potential for restoring epige-netic balance as a means to prevent cancer.     

DNA甲基化在药物效应和新药研发中的研究进展

DNA甲基化对药物作用的影响日渐受到关注。许多编码药物代谢酶、药物转运体、核受体及药物靶点的基因受DNA甲基化调控。DNA甲基化在影响细胞色素P450酶(CYP450)的表达水平上起着重要的作用,而CYP450酶系催化多种药物代谢反应,能显著影响药物疗效。目前的研究也发现DNA甲基化水平在个体间的差异与药物疗效和不良反应在个体间的差异是紧密相关的。DNA甲基化状态会受药物作用影响,进而引起不同程度的药物不良反应。近年来,以DNA甲基化为靶向的药物研发呈增长态势,DNA甲基转移酶抑制剂对肿瘤等重大疾病治疗具决定性作用。临床试验结果显示,DNA甲基化药物治疗已在改善药物疗效、稳定药理作用及减少药物不良反应上初见成效。DNA甲基化可能成为早期预测药物效应的潜在生物标记,将成为实现临床个体化用药的有力工具。     

天花粉蛋白对宫颈癌Caski细胞DNMT1基因的表达和酶活性的影响

目的研究天花粉蛋白(trichosanthin,TCS)对宫颈癌Caski细胞DNMT1基因的表达和酶活性的影响,并探讨天花粉蛋白抗宫颈癌及去甲基化机制,寻找新型去甲基化药物。方法应用RT-PCR、实时荧光定量PCR和Western免疫印迹分析检测天花粉蛋白对宫颈癌Caski细胞DNMTI基因表达的影响;应用DNMT1酶活性试剂盒检测天花粉蛋白对DNMT1酶活性的影响。结果经天花粉蛋白处理后,Caski细胞中DNM1基因mRNA及蛋白表达水平降低,体外酶活性分析发现,TCS对DNMT1酶活性有直接抑制作用。结论天花粉蛋白去甲基化的作用可能是通过抑制DNMTs的活性而实现的;天花粉蛋白有可能是新型的DNMTs抑制剂,具有潜在的临床应用价值。