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An updated patent review of metallo-β-lactamase inhibitors (2020-2023). 金属-β-内酰胺酶抑制剂的最新专利综述(2020-2023)。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-07-01 Epub Date: 2023-11-06 DOI: 10.1080/13543776.2023.2262763
Elsa Denakpo, Thierry Naas, Bogdan I Iorga

Introduction: Metallo-β-lactamases (MBLs) are enzymes produced by bacteria that confer resistance to most β-lactam antibiotics, including carbapenems, which have the broadest spectrum of activity. This resistance mechanism poses a significant threat to public health as it drastically reduces treatment options for severe bacterial infections. Developing effective inhibitors against MBLs is crucial to restore susceptibility to β-lactam antibiotics.

Areas covered: This review aims to provide an updated analysis of patents describing novel MBL inhibitors and their potential therapeutic applications that were filed between January 2020 and May 2023.

Expert opinion: Significant advancements were made in the development of selective MBL inhibitors with zinc-binding and zinc-chelating mechanisms of action. Dual inhibitors, targeting simultaneously both serine-β-lactamases (SBLs) and MBLs, represent an interesting alternative approach that is increasingly pertinent for the treatment of infections involving multiple β-lactamases from different Ambler classes. Most examples of MBL-specific inhibitors were focused on the treatment of MBL-mediated infections in Enterobacterales, where IMP-1 was a more difficult target compared with VIM-1 or NDM-1, and much less on Pseudomonas aeruginosa or Acinetobacter baumannii, which are more challenging to address.

引言:金属β-内酰胺酶(MBLs)是由细菌产生的酶,对大多数β-内内酰胺类抗生素产生耐药性,包括碳青霉烯类抗生素,它们具有最广泛的活性。这种耐药性机制对公众健康构成了重大威胁,因为它大大减少了严重细菌感染的治疗选择。开发有效的MBL抑制剂对于恢复对β-内酰胺类抗生素的易感性至关重要。涵盖领域:本综述旨在对2020年1月至2023年5月期间提交的描述新型MBL抑制剂及其潜在治疗应用的专利进行最新分析。专家意见:在开发具有锌结合和锌螯合作用机制的选择性MBL抑制剂方面取得了重大进展。同时靶向丝氨酸-β-内酰胺酶(SBLs)和MBL的双重抑制剂代表了一种有趣的替代方法,该方法越来越适用于治疗涉及不同Ambler类别的多种β-内酶的感染。MBL特异性抑制剂的大多数例子都集中在肠杆菌中MBL介导的感染的治疗上,其中IMP-1与VIM-1或NDM-1相比是更困难的靶点,而对铜绿假单胞菌或鲍曼不动杆菌的治疗则要少得多,这更难解决。
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引用次数: 0
Recent advances on patents of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors as antimalarial agents. 恶性疟原虫二氢乳清酸脱氢酶(PfDHODH)抑制剂作为抗疟药物专利的最新进展。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-07-01 Epub Date: 2023-11-28 DOI: 10.1080/13543776.2023.2280596
Pinky Gehlot, Vivek K Vyas

Introduction: Pyrimidine nucleotides are essential for the parasite's growth and replication. Parasites have only a de novo pathway for the biosynthesis of pyrimidine nucleotides. Dihydroorotate dehydrogenase (DHODH) enzyme is involved in the rate-limiting step of the pyrimidine biosynthesis pathway. DHODH is a biochemical target for the discovery of new antimalarial agents.

Area covered: This review discussed the development of patented PfDHODH inhibitors published between 2007 and 2023 along with their chemical structures and activities.

Expert opinion: PfDHODH enzyme is involved in the rate-limiting fourth step of the pyrimidine biosynthesis pathway. Thus, inhibition of PfDHODH using species-selective inhibitors has drawn much attention for treating malaria because they inhibit parasite growth without affecting normal human functions. Looking at the current scenario of antimalarial drug resistance with most of the available antimalarial drugs, there is a huge need for targeted newer agents. Newer agents with unique mechanisms of action may be devoid of drug toxicity, adverse effects, and the ability of parasites to quickly gain resistance, and PfDHODH inhibitors can be those newer agents. Many PfDHODH inhibitors were patented in the past, and the dependency of Plasmodium on de novo pyrimidine provided a new approach for the development of novel antimalarial agents.

引言:嘧啶核苷酸对寄生虫的生长和复制至关重要。寄生虫只有嘧啶核苷酸生物合成的从头途径。二氢乳清酸脱氢酶(DHODH)参与嘧啶生物合成途径的限速步骤。DHODH是发现新的抗疟药物的生化靶点。涵盖领域:本综述讨论了2007年至2023年间发表的PfDHODH专利抑制剂的开发及其化学结构和活性。专家意见:PfDHODH酶参与嘧啶生物合成途径的限速第4步。因此,使用物种选择性抑制剂抑制PfDHODH在治疗疟疾方面引起了广泛关注,因为它们在不影响正常人体功能的情况下抑制寄生虫生长。从目前大多数可用抗疟药物的抗疟耐药性来看,对靶向新药物的需求巨大。具有独特作用机制的新型药物可能没有药物毒性、副作用和寄生虫快速获得耐药性的能力,而PfDHODH抑制剂可能就是这些新型药物。许多PfDHODH抑制剂过去都获得了专利,疟原虫对从头嘧啶的依赖性为开发新型抗疟药物提供了新的途径。
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引用次数: 0
Conjugates of monocyclic β-lactams and siderophore mimetics: a patent evaluation (WO2023023393). 单环β-内酰胺和铁载体模拟物的缀合物:专利评估(WO2023023393)。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-07-01 Epub Date: 2023-11-06 DOI: 10.1080/13543776.2023.2262135
Alen Krajnc, Stanislav Gobec

Introduction: β-Lactams, which include monobactams, remain the most important class of antibiotics worldwide. Aztreonam, the only monobactam in clinical use, has remarkable activity against many Gram-negative bacteria, but limited activity against some of the most problematic multidrug-resistant (MDR) pathogens, such as MDR Pseudomonas aeruginosa and Acinetobacter baumannii co-expressing extended-spectrum- and metallo-β-lactamases, which can inactivate aztreonam by hydrolysis.

Areas covered: Structurally novel siderophore-conjugated aztreonam derivatives with improved antibacterial properties against several high-priority pathogens are claimed. This invention reports that sidechain extension of aztreonam is tolerated; the coupling of its aminothiazoloxime carboxylic acid part with a siderophore mimetic significantly improved the antibacterial activity against several problematic strains, including MDR A. baumannii isolates with carbapenemase/cephalosporinase activity.

Expert opinion: Finding new strategies to tackle bacterial resistance to β-lactam antibiotics is critical. Considering that β lactams are validated and safe drugs, this research may stimulate the field to develop new ideas in the arena of antimicrobial drug discovery, particularly with respect to siderophore mimetics.

引言:β-内酰胺,包括单体酰胺,仍然是世界上最重要的一类抗生素。氨曲南是临床上唯一使用的单体菌,对许多革兰氏阴性菌具有显著的活性,但对一些最有问题的耐多药(MDR)病原体的活性有限,如耐多药铜绿假单胞菌和鲍曼不动杆菌共表达超广谱和金属β-内酰胺酶,它们可以通过水解灭活氨曲南。所涵盖的领域:声称结构新颖的铁载体偶联氨曲南衍生物对几种高度优先的病原体具有改进的抗菌性能。本发明报道了氨曲南的侧链延伸是可耐受的;氨基噻唑肟羧酸部分与铁载体模拟物的偶联显著提高了对几种有问题菌株的抗菌活性,包括具有碳青霉烯酶/头孢菌素酶活性的耐多药鲍曼分离株。专家意见:找到解决细菌对β-内酰胺类抗生素耐药性的新策略至关重要。考虑到β内酰胺是经过验证和安全的药物,这项研究可能会激发该领域在抗菌药物发现领域,特别是在铁载体模拟物方面发展新的想法。
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引用次数: 0
CDC7 kinase inhibitors: a survey of recent patent literature (2017-2022). CDC7激酶抑制剂:近期专利文献综述(2017-2022)。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-07-01 Epub Date: 2023-11-06 DOI: 10.1080/13543776.2023.2262138
Takayuki Irie, Masaaki Sawa

Introduction: CDC7 is a serine/threonine kinase which plays an important role in DNA replication. Inhibition of CDC7 in cancer cells causes lethal S phase or M phase progression, whereas inhibition of CDC7 in normal cells does not cause cell death and only leads to cell cycle arrest at the DNA replication checkpoint. Therefore, CDC7 has been recognized as a potential target for novel therapeutic interventions in cancers.

Areas covered: Patent literature claiming novel small molecule compounds inhibiting CDC7 disclosed from 2017 to 2022.

Expert opinion: Despite the indisputable positive impact of CDC7 as a drug target, there have been reported only a handful of chemical scaffolds as CDC7 inhibitors. Several CDC7 inhibitors have been progressed into clinical trials for cancer treatments, but they did not result in satisfactory efficacies in those trials. One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.

简介:CDC7是一种丝氨酸/苏氨酸激酶,在DNA复制中起重要作用。在癌症细胞中抑制CDC7会导致致命的S期或M期进展,而在正常细胞中抑制CD C7不会导致细胞死亡,只会导致DNA复制检查点的细胞周期停滞。因此,CDC7已被认为是癌症新的治疗干预措施的潜在靶点。所涵盖的领域:2017年至2022年披露的声称具有抑制CDC7的新型小分子化合物的专利文献。专家意见:尽管CDC7作为药物靶点具有无可争议的积极影响,但据报道,只有少数化学支架作为CDC7抑制剂。几种CDC7抑制剂已进入癌症治疗的临床试验,但在这些试验中没有产生令人满意的疗效。失败的一个可能原因可能是剂量限制毒性,一些观察到的毒性被认为与CDC7抑制无关,这表明识别新的化学支架以消除不必要的毒性应该很重要。另一个重要因素是患者分层,这将使反应更大,而这种预测性生物标志物的识别应该是CDC7抑制剂开发成功的关键。
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引用次数: 0
The next generation of EGFR inhibitors: a patenting perspective of PROTACs based EGFR degraders. 下一代EGFR抑制剂:基于PROTACs的EGFR降解剂的专利前景。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-07-01 Epub Date: 2023-11-06 DOI: 10.1080/13543776.2023.2262176
Pengyun Li, Bingkun Li, Ning Yang, Tingting Xu, Zhibing Zheng

Introduction: Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials.

Areas covered: This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs.

Expert opinion: By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.

简介:表皮生长因子受体(EGFR)的异常表达有助于肿瘤的发展,尤其是在癌症(NSCLC)中。尽管已经开发出多种抑制剂来靶向不同的EGFR突变,并且有几种已经获得批准,但不可避免的耐药性和副作用仍然是一个挑战,这激发了新的策略。蛋白质水解靶向嵌合体(PROTACs)通过触发蛋白质降解,作为人类疾病的新疗法,其潜力越来越大。到目前为止,已经发现了各种强效和特异性EGFR PROTAC,其中一些已经进入临床试验。涵盖领域:本综述概述了2016年至2022年专利中的EGFR降解剂。它提供了所有可用EGFR PROTAC的发现策略、化学结构和分子图谱的更新。SciFinder、PubMed、Web of Science、EPO和CNIPA数据库用于搜索EGFR PROTAC的文献和专利。专家意见:通过采用PROTAC技术,已经开发出基于四代EGFR抑制剂的高效选择性EGFR降解剂,为靶向EGFR突变和克服耐药性提供了一种新的策略。尽管在体外和体内研究中取得了令人满意的结果,但它们的治疗价值仍有待更严格的临床前测试和临床研究。
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引用次数: 0
An updated patent review of GPR40/ FFAR1 modulators (2020 - present). GPR40/FFAR1调制器的最新专利审查(2020年至今)。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-07-01 Epub Date: 2023-11-28 DOI: 10.1080/13543776.2023.2272649
Qiang Ren, Yiqing Fan, Lixin Yang, Mayu Shan, Wei Shi, Hai Qian

Introduction: Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for type 2 diabetes mellitus (T2DM) because it could clinically stimulate insulin release in a glucose-dependent manner without inducing hypoglycemia. In both the pharmaceutical industry and academic community, FFAR1 agonists have attracted considerable attention.

Areas covered: The review presents a patent overview of FFAR1 modulators in 2020-2023, along with chemical structures, the biological activities and therapeutic applications of the representative compounds. Our patent survey used the major electronic databases, namely SciFinder, and Web of Science and Innojoy.

Expert opinion: Although FFAR1 agonists exhibit outstanding advantages, they are also associated with significant challenges. At present, reducing the molecular weight and overall lipophilicity and developing tissue-specific FFAR1 agonists may be the strategies for alleviating hepatotoxicity.

引言:游离脂肪酸受体1(FFAR1)是2型糖尿病(T2DM)的潜在治疗靶点,因为它在临床上可以以葡萄糖依赖的方式刺激胰岛素释放,而不会诱发低血糖。在制药行业和学术界,FFAR1激动剂都引起了相当大的关注。涵盖领域:该综述介绍了2020-2023年FFAR1调节剂的专利概述,以及代表性化合物的化学结构、生物活性和治疗应用。我们的专利调查使用了主要的电子数据库,即SciFinder、Web of Science和Innojoy。专家意见:尽管FFAR1激动剂表现出突出的优势,但它们也面临着重大挑战。目前,降低分子量和整体亲脂性,开发组织特异性FFAR1激动剂可能是减轻肝毒性的策略。
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引用次数: 0
An updated patent review of anaplastic lymphoma kinase inhibitors (2018-2022). 间变性淋巴瘤激酶抑制剂的最新专利审查(2018-2022)。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1080/13543776.2023.2216381
Deyi Ma, Mengrao Guo, Xin Zhai

Introduction: Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, has emerged as a promising drug target for multiple cancers. Up to now, a total of seven ALK inhibitors have been approved for clinical cancer treatment. However, the issue of resistance to ALK inhibitors was subsequently reported, which led to the exploration of novel generations of ALK inhibitors recently.

Areas covered: This paper provides a comprehensive review of the patent literature from 2018 to 2022 about structures, pharmacological data of small molecular ALK inhibitors, and their utilization as anticancer agents. In addition, several potential ALK inhibitors on the market or under clinical investigations are described in detail.

Expert opinion: To date, there are no ALK inhibitors that have been approved are completely free of resistance issues, which is a plight needing urgent solution. Development of new ALK inhibitors through structure modification, multi-targeted inhibitors, type-I½ and type-II binding modes, as well as PROTAC and drug conjugates are proceeding. Over the last 5 years, lorlatinib, entrectinib, and ensartinib have been approved, and an increasing number of studies on ALK inhibitors, especially on macrocyclic compounds, have demonstrated their promising therapeutic potency.

间变性淋巴瘤激酶(ALK)是胰岛素受体超家族中的一种受体酪氨酸激酶,已成为治疗多种癌症的有前途的药物靶点。截至目前,共有7种ALK抑制剂被批准用于临床癌症治疗。然而,对ALK抑制剂的耐药问题随后被报道,这导致了最近对新一代ALK抑制剂的探索。涵盖领域:本文对2018 - 2022年小分子ALK抑制剂的结构、药理数据及其作为抗癌药物的应用等专利文献进行了全面综述。此外,还详细介绍了市场上或正在临床研究中的几种潜在的ALK抑制剂。专家意见:到目前为止,还没有批准的ALK抑制剂完全没有耐药性问题,这是一个迫切需要解决的困境。通过结构修饰、多靶点抑制剂、i- 1 / 2型和ii型结合模式以及PROTAC和药物偶联物开发新的ALK抑制剂正在进行中。在过去的5年中,lorlatinib, entrectinib和恩沙替尼已经被批准,并且越来越多的关于ALK抑制剂的研究,特别是关于大环化合物的研究,已经证明了它们有希望的治疗效力。
{"title":"An updated patent review of anaplastic lymphoma kinase inhibitors (2018-2022).","authors":"Deyi Ma,&nbsp;Mengrao Guo,&nbsp;Xin Zhai","doi":"10.1080/13543776.2023.2216381","DOIUrl":"https://doi.org/10.1080/13543776.2023.2216381","url":null,"abstract":"<p><strong>Introduction: </strong>Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, has emerged as a promising drug target for multiple cancers. Up to now, a total of seven ALK inhibitors have been approved for clinical cancer treatment. However, the issue of resistance to ALK inhibitors was subsequently reported, which led to the exploration of novel generations of ALK inhibitors recently.</p><p><strong>Areas covered: </strong>This paper provides a comprehensive review of the patent literature from 2018 to 2022 about structures, pharmacological data of small molecular ALK inhibitors, and their utilization as anticancer agents. In addition, several potential ALK inhibitors on the market or under clinical investigations are described in detail.</p><p><strong>Expert opinion: </strong>To date, there are no ALK inhibitors that have been approved are completely free of resistance issues, which is a plight needing urgent solution. Development of new ALK inhibitors through structure modification, multi-targeted inhibitors, type-I½ and type-II binding modes, as well as PROTAC and drug conjugates are proceeding. Over the last 5 years, lorlatinib, entrectinib, and ensartinib have been approved, and an increasing number of studies on ALK inhibitors, especially on macrocyclic compounds, have demonstrated their promising therapeutic potency.</p>","PeriodicalId":12314,"journal":{"name":"Expert Opinion on Therapeutic Patents","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9531091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A patent review of selective CDK9 inhibitors in treating cancer. 选择性CDK9抑制剂治疗癌症的专利回顾。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1080/13543776.2023.2208747
Tizhi Wu, Xiaowei Wu, Yifan Xu, Rui Chen, Jubo Wang, Zhiyu Li, Jinlei Bian

Introduction: The dysregulation of CDK9 protein is greatly related to the proliferation and differentiation of various cancers due to its key role in the regulation of RNA transcription. Moreover, CDK9 inhibition can markedly downregulate the anti-apoptotic protein Mcl-1 which is essential for the survival of tumors. Thus, targeting CDK9 is considered to be a promising strategy for antitumor drug development, and the development of selective CDK9 inhibitors has gained increasing attention.

Areas covered: This review focuses on the development of selective CDK9 inhibitors reported in patent publications during the period 2020-2022, which were searched from SciFinder and Cortellis Drug Discovery Intelligence.

Expert opinion: Given that pan-CDK9 inhibitors may lead to serious side effects due to poor selectivity, the investigation of selective CDK9 inhibitors has attracted widespread attention. CDK9 inhibitors make some advance in treating solid tumors and possess the therapeutic potential in EGFR-mutant lung cancer. CDK9 inhibitors with short half-life and intravenous administration might result in transient target engagement and contribute to a better safety profile in vivo. However, more efforts are urgently needed to accelerate the development of CDK9 inhibitors, including the research on new binding modes between ligand and receptor or new protein binding sites.

导读:CDK9蛋白的失调与各种癌症的增殖和分化有很大的关系,因为它在RNA转录的调控中起着关键作用。此外,抑制CDK9可显著下调肿瘤存活所必需的抗凋亡蛋白Mcl-1。因此,靶向CDK9被认为是一种很有前景的抗肿瘤药物开发策略,选择性CDK9抑制剂的开发越来越受到关注。涵盖领域:本综述重点关注2020-2022年期间专利出版物中报道的选择性CDK9抑制剂的发展,这些专利出版物来自SciFinder和Cortellis Drug Discovery Intelligence。专家意见:鉴于泛CDK9抑制剂选择性差,可能导致严重的副作用,选择性CDK9抑制剂的研究受到了广泛关注。CDK9抑制剂在治疗实体肿瘤方面取得了一些进展,在egfr突变型肺癌中具有治疗潜力。半衰期短的CDK9抑制剂和静脉给药可能导致短暂的靶标结合,并有助于更好的体内安全性。然而,加速CDK9抑制剂的开发还需要更多的努力,包括研究配体与受体之间新的结合模式或新的蛋白质结合位点。
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引用次数: 3
A patent review of EZH2 inhibitors from 2017 and beyond. 2017年及以后EZH2抑制剂专利审查
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1080/13543776.2023.2206018
Guoquan Wan, Huan Feng, Chang Su, Yongxia Zhu, Lidan Zhang, Qiangsheng Zhang, Luoting Yu

Introduction: EZH2 is an important epigenetic regulator that forms the PRC2 complex with SUZ12, EED and RbAp46/48. As the key catalytic subunit of PRC2, EZH2 regulates the trimethylation of histone H3K27, which in turn promotes chromatin condensation and represses the transcription of relevant target genes. EZH2 overexpression and mutations are strictly related to tumor proliferation, invasion and metastasis. Currently, a large number of highly specific EZH2 inhibitors have been developed and some have already been in clinical trials.

Areas covered: The aim of the present review is to provide an overview of the molecular mechanisms of EZH2 inhibitors and to highlight the research advances in the patent literature published from 2017 to date. A search of the literature and patents for EZH2 inhibitors and degraders was performed using the Web of Science, SCIFinder, WIPO, USPTO, EPO and CNIPA databases.

Expert opinion: In recent years, a great number of structurally diverse EZH2 inhibitors have been identified, including EZH2 reversible inhibitors, EZH2 irreversible inhibitors, EZH2-based dual inhibitors and EZH2 degraders. Despite the multiple challenges, EZH2 inhibitors offer promising potential for the treatment of various diseases, such as cancers.

简介:EZH2是一种重要的表观遗传调控因子,与SUZ12、EED和RbAp46/48形成PRC2复合物。EZH2作为PRC2的关键催化亚基,调控组蛋白H3K27的三甲基化,从而促进染色质缩聚,抑制相关靶基因的转录。EZH2过表达和突变与肿瘤的增殖、侵袭和转移密切相关。目前,大量高特异性EZH2抑制剂已被开发出来,部分已进入临床试验阶段。涵盖领域:本综述的目的是概述EZH2抑制剂的分子机制,并重点介绍2017年至今发表的专利文献的研究进展。通过Web of Science、SCIFinder、WIPO、USPTO、EPO和CNIPA数据库检索EZH2抑制剂和降解剂的文献和专利。专家意见:近年来,发现了大量结构多样的EZH2抑制剂,包括EZH2可逆抑制剂、EZH2不可逆抑制剂、EZH2基双抑制剂和EZH2降解剂。尽管面临多重挑战,EZH2抑制剂为治疗各种疾病(如癌症)提供了有希望的潜力。
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引用次数: 0
A patent review of PRMT5 inhibitors to treat cancer (2018 - present). PRMT5抑制剂治疗癌症的专利审查(2018年至今)。
IF 6.6 2区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1080/13543776.2023.2201436
Jing Gao, Jie Yang, Shengyu Xue, Hong Ding, Hua Lin, Cheng Luo

Introduction: Protein arginine methyltransferase 5 (PRMT5) belongs to type II arginine methyltransferases. Since PRMT5 plays an essential role in mammalian cells, it can regulate various physiological functions, including cell growth and differentiation, DNA damage repair, and cell signal transduction. It is an epigenetic target with significant clinical potential and may become a powerful drug target for treating cancers and other diseases.

Areas covered: This review provides an overview of small-molecule inhibitors and their associated combined treatment strategies targeting PRMT5 in cancer treatment patents published since 2018, and also summarizes the progress made by several biopharmaceutical companies in the development, application, and clinical trials of small-molecule PRMT5 inhibitors. The data in this review come from WIPO, UniProt, PubChem, RCSB PDB, National Cancer Institute, and so on.

Expert opinion: Many PRMT5 inhibitors have been developed with good inhibitory activities, but most of them lack selectivities and are associated with adverse clinical responses. In addition, the progress was almost all based on the previously established skeleton, and more research and development of a new skeleton still needs to be done. The development of PRMT5 inhibitors with high activities and selectivities is still an essential aspect of research in recent years.

蛋白精氨酸甲基转移酶5 (Protein arginine methyltransferase 5, PRMT5)属于II型精氨酸甲基转移酶。由于PRMT5在哺乳动物细胞中起着至关重要的作用,它可以调节多种生理功能,包括细胞生长和分化、DNA损伤修复、细胞信号转导等。它是一种具有重要临床潜力的表观遗传靶点,可能成为治疗癌症和其他疾病的强有力的药物靶点。涵盖领域:本文综述了2018年以来公布的针对PRMT5的癌症治疗专利中的小分子抑制剂及其相关联合治疗策略,并总结了几家生物制药公司在小分子PRMT5抑制剂的开发、应用和临床试验方面取得的进展。本综述的数据来自WIPO, UniProt, PubChem, RCSB PDB, National Cancer Institute等。专家意见:许多PRMT5抑制剂已经被开发出来,具有良好的抑制活性,但大多数缺乏选择性,并且与不良的临床反应相关。此外,这些进展几乎都是基于先前建立的骨架,新骨架的更多研究和开发仍有待完成。开发具有高活性和选择性的PRMT5抑制剂仍然是近年来研究的一个重要方面。
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引用次数: 0
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Expert Opinion on Therapeutic Patents
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