Expert Opinion on Drug Discovery最新文献_第6页

Targeting guanine nucleotide exchange factors for novel cancer drug discovery. 以鸟嘌呤核苷酸交换因子为靶点，发现新型抗癌药物。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-17 DOI: 10.1080/17460441.2024.2368242

Sahar F Bannoura, Husain Yar Khan, Md Hafiz Uddin, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi

{"title":"Targeting guanine nucleotide exchange factors for novel cancer drug discovery.","authors":"Sahar F Bannoura, Husain Yar Khan, Md Hafiz Uddin, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi","doi":"10.1080/17460441.2024.2368242","DOIUrl":"10.1080/17460441.2024.2368242","url":null,"abstract":"Introduction: Guanine nucleotide exchange factors (GEFs) regulate the activation of small GTPases (G proteins) of the Ras superfamily proteins controlling cellular functions. Ras superfamily proteins act as 'molecular switches' that are turned 'ON' by guanine exchange. There are five major groups of Ras family GTPases: Ras, Ran, Rho, Rab and Arf, with a variety of different GEFs regulating their GTP loading. GEFs have been implicated in various diseases including cancer. This makes GEFs attractive targets to modulate signaling networks controlled by small GTPases.Areas covered: In this review, the roles and mechanisms of GEFs in malignancy are outlined. The mechanism of guanine exchange activity by GEFs on a small GTPase is illustrated. Then, some examples of GEFs that are significant in cancer are presented with a discussion on recent progress in therapeutic targeting efforts using a variety of approaches.Expert opinion: Recently, GEFs have emerged as potential therapeutic targets for novel cancer drug development. Targeting small GTPases is challenging; thus, targeting their activation by GEFs is a promising strategy. Most GEF-targeted drugs are still in preclinical development. A deeper biological understanding of the underlying mechanisms of GEF activity and utilizing advanced technology are necessary to enhance drug discovery for GEFs in cancer.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"949-959"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer. 用于治疗胃癌的唑贝妥昔单抗的临床前发现和开发。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1080/17460441.2024.2370332

Yongji Zeng, A Craig Lockhart, Ramon U Jin

{"title":"The preclinical discovery and development of zolbetuximab for the treatment of gastric cancer.","authors":"Yongji Zeng, A Craig Lockhart, Ramon U Jin","doi":"10.1080/17460441.2024.2370332","DOIUrl":"10.1080/17460441.2024.2370332","url":null,"abstract":"Introduction: Gastric cancer remains a formidable challenge in oncology with high mortality rates and few advancements in treatment. Claudin-18.2 (CLDN18.2) is a tight junction protein primarily expressed in the stomach and is frequently overexpressed in certain subsets of gastric cancers. Targeting CLDN18.2 with monoclonal antibodies, such as zolbetuximab (IMAB362), has shown promising efficacy results in combination with chemotherapy.Areas covered: The molecular cell biology of CLDN18.2 is discussed along with studies demonstrating the utility of CLDN18.2 expression as a biomarker and therapeutic target. Important clinical studies are reviewed, including Phase III trials, SPOTLIGHT and GLOW, which demonstrate the efficacy of zolbetuximab in combination with chemotherapy in patients with CLDN18.2-positive advanced gastric cancer.Expert opinion: CLDN18.2 is involved in gastric differentiation through maintenance of epithelial barrier function and coordination of signaling pathways, and its expression in gastric cancers reflects a 'gastric differentiation' program. Targeting Claudin-18.2 represents the first gastric cancer specific 'targeted' treatment. Further studies are needed to determine its role within current gastric cancer treatment sequencing, including HER2-targeted therapies and immunotherapies. Management strategies will also be needed to better mitigate zolbetuximab-related treatment side effects, including gastrointestinal (GI) toxicities.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"873-886"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450175","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

The coming of age of cyclic peptide drugs: an update on discovery technologies. 环肽药物时代的到来：发现技术的最新进展。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1080/17460441.2024.2367024

Sophia You, Glen McIntyre, Toby Passioura

{"title":"The coming of age of cyclic peptide drugs: an update on discovery technologies.","authors":"Sophia You, Glen McIntyre, Toby Passioura","doi":"10.1080/17460441.2024.2367024","DOIUrl":"10.1080/17460441.2024.2367024","url":null,"abstract":"Introduction: Cyclic peptides are an established class of pharmaceuticals, with the ability to bind to a broader range of protein targets than traditional small molecules while also being capable of oral availability and cell penetration. Historically, cyclic peptide drugs have been discovered almost exclusively through natural product mining approaches; however, the last two decades have seen the development of display screening approaches capable of rapidly identifying de novo (i.e. not natural product derived) cyclic peptide ligands to targets of interest.Areas covered: In this review, the authors describe the current clinical landscape for cyclic peptide pharmaceuticals. This article focuses on the discovery approaches that have led to the development of different classes of molecules and how the development of newer technologies, particularly phage and mRNA display, has broadened the clinical applicability of such molecules.Expert opinion: The field of de novo cyclic peptide drug discovery is reaching maturity, with the first drugs identified through display screening approaches reaching the market in recent years. Many more are in clinical trials; however, significant technical challenges remain. Technological improvements will be required over the coming years to facilitate the identification of membrane permeable cyclic peptides capable of oral availability and targeting intracellular proteins.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"961-973"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316957","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

The latest trends in peptide drug discovery and future challenges. 多肽药物发现的最新趋势和未来挑战。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI: 10.1080/17460441.2024.2365969

Laszlo Otvos

引用次数: 0

Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach. 揭示凝血酶抑制剂中氮含量和所选氮杂环的动态变化：一种 "雌雄各半 "的方法。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-08-01 Epub Date: 2024-06-19 DOI: 10.1080/17460441.2024.2368743

Vijay H Masand, Sami Al-Hussain, Abdullah Y Alzahrani, Aamal A Al-Mutairi, Arwa Sultan Alqahtani, Abdul Samad, Ahmed M Alafeefy, Rahul D Jawarkar, Magdi E A Zaki

{"title":"Unveiling dynamics of nitrogen content and selected nitrogen heterocycles in thrombin inhibitors: a ceteris paribus approach.","authors":"Vijay H Masand, Sami Al-Hussain, Abdullah Y Alzahrani, Aamal A Al-Mutairi, Arwa Sultan Alqahtani, Abdul Samad, Ahmed M Alafeefy, Rahul D Jawarkar, Magdi E A Zaki","doi":"10.1080/17460441.2024.2368743","DOIUrl":"10.1080/17460441.2024.2368743","url":null,"abstract":"Background: Despite the progress in comprehending molecular design principles and biochemical processes associated with thrombin inhibition, there is a crucial need to optimize efforts and curtail the recurrence of synthesis-testing cycles. Nitrogen and N-heterocycles are key features of many anti-thrombin drugs. Hence, a pragmatic analysis of nitrogen and N-heterocycles in thrombin inhibitors is important throughout the drug discovery pipeline. In the present work, the authors present an analysis with a specific focus on understanding the occurrence and distribution of nitrogen and selected N-heterocycles in the realm of thrombin inhibitors.Research design and methods: A dataset comprising 4359 thrombin inhibitors is used to scrutinize various categories of nitrogen atoms such as ring, non-ring, aromatic, and non-aromatic. In addition, selected aromatic and aliphatic N-heterocycles have been analyzed.Results: The analysis indicates that ~62% of thrombin inhibitors possess five or fewer nitrogen atoms. Substituted N-heterocycles have a high occurrence, like pyrrolidine (23.24%), pyridine (20.56%), piperidine (16.10%), thiazole (9.61%), imidazole (7.36%), etc. in thrombin inhibitors.Conclusions: The majority of active thrombin inhibitors contain nitrogen atoms close to 5 and a combination of N-heterocycles like pyrrolidine, pyridine, piperidine, etc. This analysis provides crucial insights to optimize the transformation of lead compounds into potential anti-thrombin inhibitors.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"991-1009"},"PeriodicalIF":6.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426625","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

Strategies for the design of analogs of auranofin endowed with anticancer potential. 设计具有抗癌潜力的乌拉诺芬类似物的策略。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-27 DOI: 10.1080/17460441.2024.2355329

Valentina Vitali, Lara Massai, Luigi Messori

{"title":"Strategies for the design of analogs of auranofin endowed with anticancer potential.","authors":"Valentina Vitali, Lara Massai, Luigi Messori","doi":"10.1080/17460441.2024.2355329","DOIUrl":"10.1080/17460441.2024.2355329","url":null,"abstract":"Introduction: Auranofin (AF) is a well-established, FDA-approved, antiarthritic gold drug that is currently being reevaluated for a variety of therapeutic indications through drug repurposing. AF has shown great promise as a potential anticancer agent and has been approved for a few clinical trials in cancer. The renewed interest in AF has led to extensive research into the design, preparation and biological evaluation of auranofin analogs, which may have an even better pharmacological profile than the parent drug.Areas covered: This article reviews the strategies for chemical modification of the AF scaffold. Several auranofin analogs have been prepared and characterized for medical application in the field of cancer treatment over the last 20 years. Some emerging structure-function relationships are proposed and discussed.Expert opinion: The chemical modification of the AF scaffold has been the subject of intense activity in recent years and this strategy has led to the preparation and evaluation of several AF analogs. The case of iodauranofin is a particularly promising example. The availability of homogeneous biological data for a group of AF derivatives allows some initial structure-function relationships to be proposed, which may inspire the design and synthesis of new and better AF analogs for cancer treatment.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"855-867"},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156883","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

Using induced pluripotent stem cells for drug discovery in arrhythmias. 利用诱导多能干细胞发现治疗心律失常的药物。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-02 DOI: 10.1080/17460441.2024.2360420

Diogo Teles, Barry M Fine

{"title":"Using induced pluripotent stem cells for drug discovery in arrhythmias.","authors":"Diogo Teles, Barry M Fine","doi":"10.1080/17460441.2024.2360420","DOIUrl":"10.1080/17460441.2024.2360420","url":null,"abstract":"Introduction: Arrhythmias are disturbances in the normal rhythm of the heart and account for significant cardiovascular morbidity and mortality worldwide. Historically, preclinical research has been anchored in animal models, though physiological differences between these models and humans have limited their clinical translation. The discovery of human induced pluripotent stem cells (iPSC) and subsequent differentiation into cardiomyocyte has led to the development of new in vitro models of arrhythmias with the hope of a new pathway for both exploration of pathogenic variants and novel therapeutic discovery.Areas covered: The authors describe the latest two-dimensional in vitro models of arrhythmias, several examples of the use of these models in drug development, and the role of gene editing when modeling diseases. They conclude by discussing the use of three-dimensional models in the study of arrythmias and the integration of computational technologies and machine learning with experimental technologies.Expert opinion: Human iPSC-derived cardiomyocytes models have significant potential to augment disease modeling, drug discovery, and toxicity studies in preclinical development. While there is initial success with modeling arrhythmias, the field is still in its nascency and requires advances in maturation, cellular diversity, and readouts to emulate arrhythmias more accurately.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"827-840"},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The preclinical discovery and development of atogepant for migraine prophylaxis. 用于偏头痛预防的阿托吉潘的临床前发现和开发。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-10 DOI: 10.1080/17460441.2024.2365379

Carlo Baraldi, Dagmar Beier, Paolo Martelletti, Lanfranco Pellesi

{"title":"The preclinical discovery and development of atogepant for migraine prophylaxis.","authors":"Carlo Baraldi, Dagmar Beier, Paolo Martelletti, Lanfranco Pellesi","doi":"10.1080/17460441.2024.2365379","DOIUrl":"10.1080/17460441.2024.2365379","url":null,"abstract":"Introduction: Atogepant is a selective calcitonin gene-related peptide (CGRP) receptor antagonist that is utilized in adults for the prevention of episodic and chronic migraine. Cumulative findings support the involvement of CGRP in migraine pathophysiology, and atogepant functions by competitively antagonizing CGRP receptors, which results in the inhibition of trigeminovascular nociception. The mechanism of action addresses the cause of migraine pain, providing an effective preventive treatment option.Areas covered: The key milestones in its development, including preclinical achievements, phase I, II, and III clinical trials, and regulatory approvals are reviewed. Additionally, clinical efficacy, safety profile, and tolerability of atogepant are discussed. The literature review is based on a comprehensive search of English peer-reviewed articles from various electronic databases, including PubMed and ClinicalTrials.gov.Expert opinion: The development of atogepant represents a significant breakthrough in migraine prevention, particularly due to its improved safety profile that reduces the risk of liver injury, which was a major limitation of first-generation gepants. Drug-drug interaction studies with atogepant highlight the necessity for more inclusive study populations. Given that migraine disproportionately affects females, future clinical development programs should include diverse patient demographics to ensure the findings are generalizable to all individuals suffering from migraine.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"783-788"},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295863","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

Data processing for high-throughput mass spectrometry in drug discovery. 药物发现中的高通量质谱数据处理。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-05-24 DOI: 10.1080/17460441.2024.2354871

Chang Liu, Hui Zhang

{"title":"Data processing for high-throughput mass spectrometry in drug discovery.","authors":"Chang Liu, Hui Zhang","doi":"10.1080/17460441.2024.2354871","DOIUrl":"10.1080/17460441.2024.2354871","url":null,"abstract":"Introduction: High-throughput mass spectrometry that could deliver > 10 times faster sample readout speed than traditional LC-based platforms has emerged as a powerful analytical technique, enabling the rapid analysis of complex biological samples. This increased speed of MS data acquisition has brought a critical demand for automatic data processing capabilities that should match or surpass the speed of data acquisition. Those data processing capabilities should serve the different requirements of drug discovery workflows.Areas covered: This paper introduced the key steps of the automatic data processing workflows for high-throughput MS technologies. Specific examples and requirements are detailed for different drug discovery applications.Expert opinion: The demand for automatic data processing in high-throughput mass spectrometry is driven by the need to keep pace with the accelerated speed of data acquisition. The seamless integration of processing capabilities with LIMS, efficient data review mechanisms, and the exploration of future features such as real-time feedback, automatic method optimization, and AI model training is crucial for advancing the drug discovery field. As technology continues to evolve, the synergy between high-throughput mass spectrometry and intelligent data processing will undoubtedly play a pivotal role in shaping the future of high-throughput drug discovery applications.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"815-825"},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086477","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

Computer-aided drug discovery strategies for novel therapeutics for prostate cancer leveraging next-generating sequencing data. 利用下一代测序数据发现前列腺癌新型疗法的计算机辅助药物发现策略。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2024-07-01 Epub Date: 2024-06-11 DOI: 10.1080/17460441.2024.2365370

Weijie Zhang, R Stephanie Huang

{"title":"Computer-aided drug discovery strategies for novel therapeutics for prostate cancer leveraging next-generating sequencing data.","authors":"Weijie Zhang, R Stephanie Huang","doi":"10.1080/17460441.2024.2365370","DOIUrl":"10.1080/17460441.2024.2365370","url":null,"abstract":"Introduction: Prostate cancer (PC) is the most common malignancy and accounts for a significant proportion of cancer deaths among men. Although initial therapy success can often be observed in patients diagnosed with localized PC, many patients eventually develop disease recurrence and metastasis. Without effective treatments, patients with aggressive PC display very poor survival. To curb the current high mortality rate, many investigations have been carried out to identify efficacious therapeutics. Compared to de novo drug designs, computational methods have been widely employed to offer actionable drug predictions in a fast and cost-efficient way. Particularly, powered by an increasing availability of next-generation sequencing molecular profiles from PC patients, computer-aided approaches can be tailored to screen for candidate drugs.Areas covered: Herein, the authors review the recent advances in computational methods for drug discovery utilizing molecular profiles from PC patients. Given the uniqueness in PC therapeutic needs, they discuss in detail the drug discovery goals of these studies, highlighting their translational values for clinically impactful drug nomination.Expert opinion: Evolving molecular profiling techniques may enable new perspectives for computer-aided approaches to offer drug candidates for different tumor microenvironments. With ongoing efforts to incorporate new compounds into large-scale high-throughput screens, the authors envision continued expansion of drug candidate pools.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"841-853"},"PeriodicalIF":6.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0