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Type II & III inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update. 肌球蛋白受体激酶(Trk)的 II 型和 III 型抑制剂:2020-2022 年专利更新。
IF 5.4 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-04-01 Epub Date: 2024-05-30 DOI: 10.1080/13543776.2024.2358818
Petar Iliev, Carolin Jaworski, Carmen Wängler, Björn Wängler, Brent D G Page, Ralf Schirrmacher, Justin J Bailey

Introduction: The Trk family proteins are membrane-bound kinases predominantly expressed in neuronal tissues. Activated by neurotrophins, they regulate critical cellular processes through downstream signaling pathways. Dysregulation of Trk signaling can drive a range of diseases, making the design and study of Trk inhibitors a vital area of research. This review explores recent advances in the development of type II and III Trk inhibitors, with implications for various therapeutic applications.

Areas covered: Patents covering type II and III inhibitors targeting the Trk family are discussed as a complement of the previous review, Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update. Relevant patents were identified using the Web of Science database, Google, and Google Patents.

Expert opinion: While type II and III Trk inhibitor development has advanced more gradually compared to their type I counterparts, they hold significant promise in overcoming resistance mutations and achieving enhanced subtype selectivity - a critical factor in reducing adverse effects associated with pan-Trk inhibition. Recent interdisciplinary endeavors have marked substantial progress in the design of subtype selective Trk inhibitors, with impressive success heralded by the type III inhibitors. Notably, the emergence of mutant-selective Trk inhibitors introduces an intriguing dimension to the field, offering precise treatment possibilities.

引言Trk 家族蛋白是主要在神经元组织中表达的膜结合激酶。在神经营养素的激活下,它们通过下游信号通路调节关键的细胞过程。Trk 信号传导失调可导致一系列疾病,因此设计和研究 Trk 抑制剂是一个重要的研究领域。本综述探讨了开发 II 型和 III 型 Trk 抑制剂的最新进展,以及对各种治疗应用的影响:本综述讨论了针对Trk家族的II型和III型抑制剂的专利,作为上一篇综述《肌球蛋白受体激酶(Trk)的I型抑制剂:2020-2022年专利更新》的补充。相关专利是通过科学网数据库、谷歌和谷歌专利来确定的:虽然II型和III型Trk抑制剂的开发与I型抑制剂相比进展较为缓慢,但它们在克服耐药性突变和增强亚型选择性方面大有可为--这是减少与泛Trk抑制相关的不良反应的一个关键因素。最近的跨学科努力标志着亚型选择性 Trk 抑制剂的设计取得了重大进展,III 型抑制剂取得了令人瞩目的成功。值得注意的是,突变选择性 Trk 抑制剂的出现为这一领域引入了一个有趣的维度,提供了精确治疗的可能性。
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引用次数: 0
Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors - a review of patent literature from 2019-June 2023. 合成致死:靶向SMARCA2溴链降解SMARCA4缺陷肿瘤--2019年至2023年6月专利文献综述。
IF 5.4 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-04-01 Epub Date: 2024-05-20 DOI: 10.1080/13543776.2024.2355258
Esther C Y Lee, Kyle D Reichl, Ariamala Gopalsamy

Introduction: SMARCA2 and SMARCA4 are subunits of the SWI/SNF complex which is a chromatin remodeling complex and a key epigenetic regulator that facilitates gene expression. Tumors with loss of function mutations in SMARCA4 rely on SMARCA2 for cell survival and this synthetic lethality is a potential therapeutic strategy to treat cancer.

Areas covered: The current review focuses on patent applications that claim proteolysis-targeting chimeras (PROTAC) degraders that bind the bromodomain site of SMARCA2 and are published between January 2019-June 2023. A total of 29 applications from 9 different applicants were evaluated.

Expert opinion: SMARCA2/4 bromodomain inhibitors do not lead to desired effects on cancer proliferation; however, companies have converted bromodomain binders into PROTACs to degrade the protein, with a preference for SMARCA2 over SMARCA4. Selective degradation of SMARCA2 is most likely required to be efficacious in the SMARCA4-deficient setting, while allowing for sufficient safety margin in normal tissues. With several patent applications disclosed recently, interest in targeting SMARCA2 should continue, especially with a selective SMARCA2 PROTAC now in the clinic from Prelude Therapeutics. The outcome of the clinical trials will influence the evolution of selective SMARCA2 PROTACs development.

引言SMARCA2和SMARCA4是SWI/SNF复合体的亚基,SWI/SNF复合体是染色质重塑复合体,也是促进基因表达的关键表观遗传调节因子。SMARCA4功能缺失突变的肿瘤细胞依赖SMARCA2存活,这种合成致死性是治疗癌症的潜在治疗策略:本综述重点关注2019年1月至2023年6月期间公布的、声称具有蛋白水解靶向嵌合体(PROTAC)降解剂的专利申请,这些降解剂结合了SMARCA2的溴结构域位点。共有来自9个不同申请人的29份申请接受了评估:SMARCA2/4溴链抑制剂不会对癌症增殖产生预期效果;然而,一些公司已将溴链结合剂转化为PROTACs,以降解蛋白质,其中SMARCA2比SMARCA4更受青睐。选择性降解 SMARCA2 很可能是在 SMARCA4 缺失的情况下有效的必要条件,同时也为正常组织留出了足够的安全余地。随着最近几项专利申请的披露,人们对靶向 SMARCA2 的兴趣应该会持续下去,尤其是 Prelude Therapeutics 公司的一种选择性 SMARCA2 PROTAC 已进入临床。临床试验的结果将影响选择性 SMARCA2 PROTACs 的发展。
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引用次数: 0
A patent review of P2X7 receptor antagonists to treat inflammatory diseases (2018-present). 治疗炎症性疾病的 P2X7 受体拮抗剂专利回顾(2018 年至今)。
IF 5.4 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-04-01 Epub Date: 2024-06-11 DOI: 10.1080/13543776.2024.2363885
Jamshed Iqbal, Sehrish Bano, Imtiaz Ali Khan, Qing Huang

Introduction: The purinergic P2X7 receptor (P2X7R) is expressed on the surface of many different types of cells, including immune cells. Targeting P2X7R with antagonists has been studied for its potential therapeutic effects in a variety of inflammatory illnesses.

Area covered: Many chemical substances, including carboxamides, benzamides and nitrogen containing heterocyclic derivatives have demonstrated promising inhibitory potential for P2X7 receptor. The chemistry and clinical applications of P2X7R antagonists patented from 2018- present are discussed in this review.

Expert opinion: Purinergic receptor inhibitor discovery and application has demonstrated the potential for therapeutic intervention, as demonstrated by pharmacological research. Few chemical modalities have been authorized for use in clinical settings, despite the fact that breakthroughs in crystallography and chemical biology have increased the knowledge of purinergic signaling and its consequences in disease. The many research projects and pharmaceutical movements that sustain dynamic P2X receptor programs over decades are evidence of the therapeutic values and academic persistence in purinergic study. P2X7R is an intriguing therapeutic target and possible biomarker for inflammation. Although several companies like Merck and AstraZeneca have published patents on P2X3 antagonists, the search for P2X7R antagonists has not stopped. Numerous pharmaceutical companies have disclosed different scaffolds, and some molecules are presently being studied in clinical studies.

简介嘌呤能 P2×7 受体表达于许多不同类型的细胞表面,包括免疫细胞。用拮抗剂靶向 P2×7 受体对多种炎症性疾病具有潜在的治疗作用。它在控制炎症反应中起着至关重要的作用:许多化学物质,包括羧酰胺、苯酰胺、含氮杂环衍生物和金刚烷羰基硫脲化合物,都对 P2×7 受体具有良好的抑制潜力。本综述讨论了2018年至今获得专利的P2×7受体拮抗剂的化学和临床应用:嘌呤能受体抑制剂的发现和应用已显示出治疗干预的潜力,药理学研究也证明了这一点。尽管晶体学和化学生物学方面的突破增加了人们对嘌呤能信号转导及其疾病后果的了解,但授权用于临床的化学模式却寥寥无几。数十年来,许多研究项目和制药运动维持着活跃的 P2X 受体计划,这证明了嘌呤能研究的治疗价值和学术坚持。P2×7 受体是一个令人感兴趣的治疗靶点,也可能是癌症、疼痛和炎症的生物标志物。尽管默克(Merck)和阿斯利康(AstraZeneca)等几家公司已经公布了 P2×3 拮抗剂的专利,但对 P2×7receptor (P2X7R) 拮抗剂的探索并未停止。许多制药公司已经公开了不同的支架,其中一些分子目前正在进行临床研究。
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引用次数: 0
Protein tyrosine phosphatase inhibitors: a patent review and update (2012-2023). 蛋白酪氨酸磷酸酶抑制剂:专利回顾与更新(2012-2023 年)。
IF 5.4 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-04-01 Epub Date: 2024-06-19 DOI: 10.1080/13543776.2024.2362203
Lakshmi Mounika Kelam, Vaishnavi Chhabra, Sarika Dhiman, Deevena Kumari, M Elizabeth Sobhia

Introduction: Protein tyrosine phosphatases (PTPs), essential and evolutionarily highly conserved enzymes, govern cellular functions by modulating tyrosine phosphorylation, a pivotal post-translational modification for signal transduction. The recent strides in phosphatase drug discovery, leading to the identification of selective modulators for enzymes, restoring interest in the therapeutic targeting of protein phosphatases.

Areas covered: The compilation of patents up to the year 2023 focuses on the efficacy of various classes of Tyrosine phosphatases and their inhibitors, detailing their chemical structure and biochemical characteristics. These findings have broad implications, as they can be applied to treating diverse conditions like cancer, diabetes, autoimmune disorders, and neurological diseases. The search for scientific articles and patent literature was conducted using well known different platforms to gather information up to 2023.

Expert opinion: The latest improvements in protein tyrosine phosphatase (PTP) research include the discovery of new inhibitors targeting specific PTP enzymes, with a focus on developing allosteric site covalent inhibitors for enhanced efficacy and specificity. These advancements have not only opened up new possibilities for therapeutic interventions in various disease conditions but also hold the potential for innovative treatments. PTPs offer promising avenues for drug discovery efforts and innovative treatments across a spectrum of health conditions.

导言:蛋白酪氨酸磷酸酶(PTPs)是一种重要的、在进化过程中高度保守的酶,通过调节酪氨酸磷酸化这一信号转导的关键翻译后修饰来控制细胞功能。最近在磷酸酶药物发现方面取得了长足进步,从而确定了酶的选择性调节剂,恢复了对蛋白磷酸酶靶向治疗的兴趣:截至 2023 年的专利汇编侧重于各类酪氨酸磷酸酶及其抑制剂的功效,详细介绍了它们的化学结构和生化特性。这些发现具有广泛的意义,因为它们可用于治疗癌症、糖尿病、自身免疫性疾病和神经系统疾病等多种疾病。我们利用知名的不同平台对科学文章和专利文献进行了搜索,以收集截至 2023 年的信息:蛋白酪氨酸磷酸酶(PTP)研究的最新进展包括发现了针对特定 PTP 酶的新型抑制剂,重点是开发异位位点共价抑制剂,以提高疗效和特异性。这些进展不仅为各种疾病的治疗干预开辟了新的可能性,而且还为创新治疗带来了潜力。PTP 为药物发现工作和各种健康状况的创新治疗提供了前景广阔的途径。
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引用次数: 0
HDAC3 inhibitors: a patent review of their broad-spectrum applications as therapeutic agents. HDAC3 抑制剂:关于其作为治疗剂的广泛应用的专利综述。
IF 5.4 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-04-01 Epub Date: 2024-06-25 DOI: 10.1080/13543776.2024.2363890
Thabo Brighton Makgoba, Erika Kapp, Samuel Egieyeh, Jacques Joubert

Introduction: Histone deacetylases (HDACs) are a class of zinc-dependent enzymes. They maintain acetylation homeostasis, with numerous biological functions and are associated with many diseases. HDAC3 strictly requires multi-subunit complex formation for activity. It is associated with the progression of numerous non-communicable diseases. Its widespread involvement in diseases makes it an epigenetic drug target. Preexisting HDAC3 inhibitors have many uses, highlighting the need for continued research in the discovery of HDAC3-selective inhibitors.

Area covered: This review provides an overview of 24 patents published from 2010 to 2023, focusing on compounds that inhibit the HDAC3 isoenzyme.

Expert opinion: HDAC3-selective inhibitors - pivotal for pharmacological applications, as single or combination therapies - are gaining traction as a strategy to move away from complications laden pan-HDAC inhibitors. Moreover, there is an unmet need for HDAC3 inhibitors with alternative zinc-binding groups (ZBGs) because some preexisting ZBGs have limitations related to toxicity and side effects. Difficulties in achieving HDAC3 selectivity may be due to isoform selectivity. However, advancements in computer-aided drug design and experimental data of HDAC3 3D co-crystallized models could lead to the discovery of novel HDAC3-selective inhibitors, which bear alternative ZBGs with balanced selectivity for HDAC3 and potency.

简介组蛋白去乙酰化酶(HDACs)是一类锌依赖酶。它们维持乙酰化平衡,具有多种生物学功能,并与许多疾病相关。HDAC3 的活性严格需要多亚基复合物的形成。它与许多非传染性疾病的进展有关。HDAC3 与疾病的广泛关系使其成为表观遗传药物的靶点。现有的 HDAC3 抑制剂有多种用途,因此需要继续研究发现 HDAC3 选择性抑制剂:本综述概述了 2010-2023 年间发表的 24 项专利,重点关注抑制 HDAC3 同工酶的化合物:HDAC3选择性抑制剂--作为单药或联合疗法的关键药理应用--作为一种摒弃充满并发症的泛HDAC抑制剂的策略,正受到越来越多的关注。此外,对具有替代锌结合基团(ZBG)的 HDAC3 抑制剂的需求尚未得到满足,因为现有的一些 ZBG 具有毒性和副作用方面的局限性。实现 HDAC3 选择性的困难可能是由于同工酶选择性造成的。然而,计算机辅助药物设计的进步和 HDAC3 三维共晶体模型的实验数据可能会导致新型 HDAC3 选择性抑制剂的发现。这些抑制剂具有对 HDAC3 的平衡选择性和效力。
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引用次数: 0
Carbonic anhydrase and bacterial metabolism: a chance for antibacterial drug discovery 碳酸酐酶与细菌新陈代谢:抗菌药物发现的契机
IF 6.6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-03-20 DOI: 10.1080/13543776.2024.2332663
Clemente Capasso, Claudiu T. Supuran
Carbonic anhydrases (CAs, EC 4.2.1.1) play a pivotal role in the regulation of carbon dioxide , bicarbonate, and hydrogen ions within bacterial cells, ensuring pH homeostasis and facilitating energ...
碳酸酐酶(CAs,EC 4.2.1.1)在调节细菌细胞内的二氧化碳、碳酸氢盐和氢离子、确保 pH 值平衡和促进能量代谢方面发挥着关键作用。
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引用次数: 0
Successes and challenges in the development of BD1-selective BET inhibitors: a patent review 开发 BD1 选择性 BET 抑制剂的成功与挑战:专利回顾
IF 6.6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-03-05 DOI: 10.1080/13543776.2024.2327300
Monica Viviano, Alessandra Cipriano, Emanuele Fabbrizi, Alessandra Feoli, Sabrina Castellano, Gianluca Sbardella, Antonello Mai, Ciro Milite, Dante Rotili
Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. BET family ...
溴结构域和末端外(BET)结构域蛋白是一种转录辅因子,能识别组蛋白和非组蛋白的乙酰化赖氨酸,从而调节基因表达。BET 家族 ...
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引用次数: 0
Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023). 在抗癌研究中靶向 PI3K/AKT 信号通路:抑制剂设计和临床试验的最新进展(2020-2023 年)。
IF 6.6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-03-01 Epub Date: 2024-04-09 DOI: 10.1080/13543776.2024.2338100
Dima A Sabbah, Rima Hajjo, Sanaa K Bardaweel, Haizhen A Zhong

Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed.

Area covered: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023.

Expert opinion: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

导言:近年来,针对磷脂酰肌醇 3- 激酶/蛋白激酶-B(PI3K/AKT)信号通路的药物设计和开发取得了巨大成就。PI3K和AKT的近邻蛋白-蛋白相互作用网络显示了这些靶蛋白之间的相互作用,可用于药物发现。在这篇综述中,我们讨论了过去三年中 PI3K/AKT 抑制剂的药物设计和临床开发。我们详细回顾了根据靶蛋白分类的 35 种针对这些蛋白的抑制剂的结构、选择性、疗效和联合疗法。我们还讨论了克服耐药性和减少毒性的方法。还讨论了开发 PI3K 和 AKT 抑制剂的联合疗法和 PROTAC 的未来研究方向:本综述涵盖 2020 年至 2023 年间发表的有关 PI3K 和 AKT 抑制剂的临床试验报告和专利文献:为解决PI3K和AKT抑制剂的耐药性和药物毒性问题,设计和开发亚型选择性PI3K抑制剂或亚型选择性AKT1抑制剂以最大限度地降低毒性,或开发可形成共价键的异构药物是非常可取的。开发 PI3Kα 或 AKT 的 PROTACs 有助于减少脱靶毒性。
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引用次数: 0
A patent review on HMGB1 inhibitors for the treatment of liver diseases. 关于治疗肝病的 HMGB1 抑制剂的专利综述。
IF 6.6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-03-01 Epub Date: 2024-04-09 DOI: 10.1080/13543776.2024.2338105
Richa Raj, Pingping Shen, Boyang Yu, Jian Zhang

Introduction: HMGB1 is a non-histone chromatin protein released or secreted in response to tissue damage or infection. Extracellular HMGB1, as a crucial immunomodulatory factor, binds with several different receptors to innate inflammatory responses that aggravate acute and chronic liver diseases. The increased levels of HMGB1 have been reported in various liver diseases, highlighting that it represents a potential biomarker and druggable target for therapeutic development.

Areas covered: This review summarizes the current knowledge on the structure, function, and interacting receptors of HMGB1 and its significance in multiple liver diseases. The latest patented and preclinical studies of HMGB1 inhibitors (antibodies, peptides, and small molecules) for liver diseases are summarized by using the keywords 'HMGB1,' 'HMGB1 antagonist, HMGB1-inhibitor,' 'liver disease' in Web of Science, Google Scholar, Google Patents, and PubMed databases in the year from 2017 to 2023.

Expert opinions: In recent years, extensive research on HMGB1-dependent inflammatory signaling has discovered potent inhibitors of HMGB1 to reduce the severity of liver injury. Despite significant progress in the development of HMGB1 antagonists, few of them are approved for clinical treatment of liver-related diseases. Developing safe and effective specific inhibitors for different HMGB1 isoforms and their interaction with receptors is the focus of future research.

简介HMGB1 是一种非组蛋白染色质蛋白,在组织损伤或感染时从细胞中释放或分泌。细胞外 HMGB1 是一种重要的免疫调节因子,它与几种不同的受体结合,引起先天性炎症反应,从而加重急性和慢性肝病。各种肝病中都有 HMGB1 水平升高的报道,这表明 HMGB1 是一种潜在的生物标志物和可用于治疗开发的药物靶点:本综述总结了目前有关 HMGB1 的结构、功能、相互作用受体及其在多种肝病中的重要性的知识。以 "HMGB1"、"HMGB1拮抗剂/抑制剂"、"肝脏疾病 "为关键词,总结了2017-2023年间在Web of Science、Google Scholar、Google Patents和PubMed数据库中关于HMGB1抑制剂(抗体、多肽和小分子药物)治疗肝脏疾病的最新专利和临床前研究:近年来,对HMGB1依赖性炎症信号转导的广泛研究发现了有效的HMGB1抑制剂,可减轻肝损伤的严重程度。尽管HMGB1拮抗剂的研发取得了重大进展,但获准用于临床治疗肝脏相关疾病的拮抗剂却寥寥无几。针对不同的 HMGB1 异构体及其与受体的相互作用开发安全有效的特异性抑制剂是未来研究的重点。
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引用次数: 0
Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023). 针对表皮生长因子受体/RAS/RAF 信号通路的抗癌研究:抑制剂设计和临床试验的最新进展(2020-2023 年)。
IF 6.6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-01-01 Epub Date: 2024-03-12 DOI: 10.1080/13543776.2024.2327307
Rima Hajjo, Dima A Sabbah, Sanaa K Bardaweel, Haizhen A Zhong

Introduction: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions.

Area covered: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation.

Expert opinion: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.

涵盖领域:本综述涵盖2020年至2023年期间发表的有关表皮生长因子受体(EGFR)、KRAS和BRAF抑制剂的临床试验报告和专利文献。还包括设计和合成作为表皮生长因子受体/KRAS/BRAF降解剂的蛋白水解靶向嵌合体(PROTACs)的最新进展:为了克服目前针对表皮生长因子受体/RAS/RAF通路治疗的耐药性,设计和开发第四代表皮生长因子受体异构抑制剂是非常可取的。共价药物、异位药物、联合疗法或开发 PROTAC 降解剂仍是克服 KRAS 和 BRAF 抑制剂耐药性和毒性的主要方法。
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引用次数: 0
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Expert Opinion on Therapeutic Patents
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