Expert Opinion on Drug Discovery最新文献

The rules often neglected in current medicinal chemistry.

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-08 DOI: 10.1080/17460441.2025.2465370

Boris Cvek

引用次数: 0

The preclinical discovery and development of zanubrutinib for the treatment of chronic lymphocytic leukemia.

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-08 DOI: 10.1080/17460441.2025.2465365

Teri K Schleicher, Melanie Cohen, Solomon A Graf

{"title":"The preclinical discovery and development of zanubrutinib for the treatment of chronic lymphocytic leukemia.","authors":"Teri K Schleicher, Melanie Cohen, Solomon A Graf","doi":"10.1080/17460441.2025.2465365","DOIUrl":"https://doi.org/10.1080/17460441.2025.2465365","url":null,"abstract":"Introduction: The history of treating chronic lymphocytic leukemia (CLL) inflected in 2014 with the Food and Drug Administration's (FDA) approval of ibrutinib, the first-in-class small molecule inhibitor of the Bruton's tyrosine kinase (BTK). Zanubrutinib is a 2nd generation covalent BTK inhibitor developed and manufactured by BeiGene.Areas covered: In this review, the authors trace the arc of zanubrutinib development from the preclinical phase through the two landmark phase 3 studies in the CLL space, ALPINE and SEQUOIA. The authors cover contemporary management strategies in CLL and highlight the areas of need that zanubrutinib was designed to mitigate.Expert opinion: Zanubrutinib entered a fray of novel, exciting therapies for CLL. As the second of two 2nd generation covalent BTK inhibitors its path to prominence in CLL management was narrow. Emphasis during development on kinase selectivity and enhanced bioavailability identified a molecule with superior efficacy and tolerability; hierarchical endpoints in trial design allowed for efficient acquisition of comparative data. Zanubrutinib is endorsed by the National Comprehensive Cancer Network as a preferred, category 1 recommended treatment choice for CLL. Future efforts in combination therapies and response-directed treatment breaks will hopefully lead to still further improvements in use.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374047","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 importance of preclinical models for cholangiocarcinoma drug discovery. 临床前模型对胆管癌药物发现的重要性。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-05 DOI: 10.1080/17460441.2025.2457637

Felix J Krendl, Florian Primavesi, Rupert Oberhuber, Daniel Neureiter, Matthias Ocker, Dino Bekric, Tobias Kiesslich, Christian Mayr

{"title":"The importance of preclinical models for cholangiocarcinoma drug discovery.","authors":"Felix J Krendl, Florian Primavesi, Rupert Oberhuber, Daniel Neureiter, Matthias Ocker, Dino Bekric, Tobias Kiesslich, Christian Mayr","doi":"10.1080/17460441.2025.2457637","DOIUrl":"10.1080/17460441.2025.2457637","url":null,"abstract":"Introduction: Biliary tract cancer (BTC) comprises a clinically diverse and genetically heterogeneous group of tumors along the intra- and extrahepatic biliary system (intrahepatic and extrahepatic cholangiocarcinoma) and gallbladder cancer with the common feature of a poor prognosis, despite increasing molecular knowledge of associated genetic aberrations and possible targeted therapies. Therefore, the search for even more precise and individualized therapies is ongoing and preclinical tumor models are central to the development of such new approaches.Areas covered: The models described in the current review include simple and advanced in vitro and in vivo models, including cell lines, 2D monolayer, spheroid and organoid cultures, 3D bioprinting, patient-derived xenografts, and more recently, machine-perfusion platform-based models of resected liver specimens. All these models have individual advantages, disadvantages and limitations that need to be considered depending on the desired application.Expert opinion: In addition to potential cost limitations, availability of BTC cell types, time required for model establishment and growth success rate, the individual models differently reflect relevant characteristics such as tumor heterogeneity, spatial tumor-stroma microenvironment interactions, metabolic and nutritional gradients and immunological interactions. Therefore, a consequent combination of different models may be required to improve clinical study outcomes by strengthening the preclinical data basis.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1-12"},"PeriodicalIF":6.0,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002921","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

Animal models of Kabuki syndrome and their applicability to novel drug discovery.

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-03 DOI: 10.1080/17460441.2025.2457624

Mareike Mertens, Leen Khalife, Xiaoting Ma, Olaf Bodamer

{"title":"Animal models of Kabuki syndrome and their applicability to novel drug discovery.","authors":"Mareike Mertens, Leen Khalife, Xiaoting Ma, Olaf Bodamer","doi":"10.1080/17460441.2025.2457624","DOIUrl":"10.1080/17460441.2025.2457624","url":null,"abstract":"Introduction: Kabuki Syndrome (KS) is a rare genetic disorder characterized by distinctive facial features, intellectual disability, and multiple congenital anomalies. It is caused by pathogenic variants in the KMT2D and KDM6A genes. Despite its significant disease burden, there are currently no approved therapies for KS, highlighting the need for advanced research and therapeutic development.Areas covered: This review examines the use of animal models in KS research, including mice, fish, frogs, and nematodes. These models replicate key mechanistic and clinical aspects of Kabuki Syndrome, facilitating preclinical studies to demonstrate therapeutic efficacy. The literature search focused on identifying studies that utilized these models to investigate the pathophysiology of Kabuki Syndrome and evaluate potential treatments.Expert opinion: Refining animal models is essential to enhance their relevance to human disease and accelerate the development of effective therapies for Kabuki Syndrome. Insights from these models are invaluable in understanding underlying molecular mechanisms and identifying therapeutic targets. Continued research and collaboration are crucial to translating these findings into clinical practice, offering hope for future treatments.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1-13"},"PeriodicalIF":6.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037768","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

Investigating novel pharmacological strategies for treatment-resistant depression: focus on new mechanisms and approaches.

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-02-03 DOI: 10.1080/17460441.2025.2460674

Aline Silva de Miranda, Eliana C B Toscano, Venugopal Reddy Venna, Frederico Guilherme Graeff, Antonio Lucio Teixeira

{"title":"Investigating novel pharmacological strategies for treatment-resistant depression: focus on new mechanisms and approaches.","authors":"Aline Silva de Miranda, Eliana C B Toscano, Venugopal Reddy Venna, Frederico Guilherme Graeff, Antonio Lucio Teixeira","doi":"10.1080/17460441.2025.2460674","DOIUrl":"10.1080/17460441.2025.2460674","url":null,"abstract":"Introduction: A substantial number of patients exhibit treatment-resistant depression (TRD), posing significant challenges to clinicians. The discovery of novel molecules or mechanisms that may underlie TRD pathogenesis and antidepressant actions is highly needed.Areas covered: Using the PubMed database, the authors searched for emerging evidence of novel approaches for TRD based on experimental and human studies. Herein, the authors discuss the mechanisms underlying glutamatergic antagonists, modulators of the opioid system, and tryptamine-derivate psychedelics as well as the emerging platforms to investigate novel pharmacological targets for TRD. A search for clinical trials investigating novel agents and interventions for TRD was also conducted.Expert opinion: The understanding of the multiple pathophysiological mechanisms involved in TRD may add further value to the effective treatment, contributing to a more personalized approach. Esketamine was approved for the treatment of TRD and novel drugs with rapid antidepressant actions such as psilocybin and buprenorphine have also been investigated as potential therapeutic strategies. Over the past decades, technological advances such as omics approaches have broadened our knowledge regarding molecular and genetic underpinnings of complex conditions like TRD. Omics approaches could open new avenues for investigating glial-mediated mechanisms, including their crosstalk with neurons, as therapeutic targets in TRD.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1-15"},"PeriodicalIF":6.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064851","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 role of rodent behavioral models of schizophrenia in the ongoing search for novel antipsychotics.

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-28 DOI: 10.1080/17460441.2025.2459807

Hugo Cano-Ramírez, Kurt Leroy Hoffman

{"title":"The role of rodent behavioral models of schizophrenia in the ongoing search for novel antipsychotics.","authors":"Hugo Cano-Ramírez, Kurt Leroy Hoffman","doi":"10.1080/17460441.2025.2459807","DOIUrl":"https://doi.org/10.1080/17460441.2025.2459807","url":null,"abstract":"Introduction: Existing pharmacotherapies for schizophrenia have not progressed beyond targeting dopamine and serotonin neurotransmission. Rodent models of schizophrenia are a necessary tool for elucidating neuropathological processes and testing potential pharmacotherapies, but positive preclinical results in rodent models often do not translate to positive results in the clinic.Areas covered: The authors reviewed PubMed for studies that applied rodent behavioral models of schizophrenia to assess the antipsychotic potential of several novel pharmacotherapies currently under investigation. These included acetylcholinesterase inhibitors, muscarinic and nicotinic acetylcholine (ACh) receptor agonists and positive allosteric modulators (PAMs), histamine H3 receptor antagonist/inverse, calcium channel modulators, trace amino acid receptor (TAAR) agonists, and phosphodiesterase 10A (PDE10A) inhibitors. The authors discuss the extent to which the results of preclinical studies of these drugs in rodent models have predicted clinical efficacy.Expert opinion: Although published preclinical studies of these drugs were largely positive, clinical results were often modest or negative. This lack of correspondence is likely due to many factors, including differences in experimental design, poor translation of effective dosing from preclinical to clinical studies, and large inter-individual variation of the human population as compared to laboratory rodents. Closing the gap between preclinical and clinical studies will require strategies aimed at reducing the impact of these factors.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1-15"},"PeriodicalIF":6.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058537","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

Virtual screening: hope, hype, and the fine line in between.

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-27 DOI: 10.1080/17460441.2025.2458666

Hossam Nada, Nicholas A Meanwell, Moustafa T Gabr

{"title":"Virtual screening: hope, hype, and the fine line in between.","authors":"Hossam Nada, Nicholas A Meanwell, Moustafa T Gabr","doi":"10.1080/17460441.2025.2458666","DOIUrl":"10.1080/17460441.2025.2458666","url":null,"abstract":"Introduction: Technological advancements in virtual screening (VS) have rapidly accelerated its application in drug discovery, as reflected by the exponential growth in VS-related publications. However, a significant gap remains between the volume of computational predictions and their experimental validation. This discrepancy has led to a rise in the number of unverified 'claimed' hits which impedes the drug discovery efforts.Areas covered: This perspective examines the current VS landscape, highlighting essential practices and identifying critical challenges, limitations, and common pitfalls. Using case studies and practices, this perspective aims to highlight strategies that can effectively mitigate or overcome these challenges. Furthermore, the perspective explores common approaches for addressing pharmacodynamic and pharmacokinetic issues in optimizing VS hits.Expert opinion: VS has become a tried-and-true technique of drug discovery due to the rapid advances in computational methods and machine learning (ML) over the past two decades. Although each VS workflow varies depending on the chosen approach and methodology, integrated strategies that combine biological and in silico data have consistently yielded higher success rates. Moreover, the widespread adoption of ML has enhanced the integration of VS into the drug discovery pipeline. However, the absence of standardized evaluation criteria hinders the objective assessment of VS studies' success and the identification of optimal adoption methods.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1-18"},"PeriodicalIF":6.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037770","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 continuing importance of chemical intuition for the medicinal chemist in the era of Artificial Intelligence. 人工智能时代化学直觉对药物化学家的持续重要性。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-19 DOI: 10.1080/17460441.2025.2450785

Michael M Hann, György M Keserű

引用次数: 0

Advances in cryo-electron microscopy (cryoEM) for structure-based drug discovery. 基于结构的药物发现的低温电子显微镜（cryoEM）研究进展。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-16 DOI: 10.1080/17460441.2025.2450636

Pawel Rubach, Karolina A Majorek, Michal Gucwa, Krzysztof Murzyn, Alexander Wlodawer, Wladek Minor

{"title":"Advances in cryo-electron microscopy (cryoEM) for structure-based drug discovery.","authors":"Pawel Rubach, Karolina A Majorek, Michal Gucwa, Krzysztof Murzyn, Alexander Wlodawer, Wladek Minor","doi":"10.1080/17460441.2025.2450636","DOIUrl":"10.1080/17460441.2025.2450636","url":null,"abstract":"Introduction: Macromolecular X-ray crystallography (XRC), nuclear magnetic resonance (NMR), and cryo-electron microscopy (cryoEM) are the primary techniques for determining atomic-level, three-dimensional structures of macromolecules essential for drug discovery. With advancements in artificial intelligence (AI) and cryoEM, the Protein Data Bank (PDB) is solidifying its role as a key resource for 3D macromolecular structures. These developments underscore the growing need for enhanced quality metrics and robust validation standards for experimental structures.Areas covered: This review examines recent advancements in cryoEM for drug discovery, analyzing structure quality metrics, resolution improvements, metal-ligand and water molecule identification, and refinement software. It compares cryoEM with other techniques like XRC and NMR, emphasizing the global expansion of cryoEM facilities and its increasing significance in drug discovery.Expert opinion: CryoEM is revolutionizing structural biology and drug discovery, particularly for large, complex structures in induced proximity and antibody-antigen interactions. It supports vaccine design, CAR T-cell optimization, gene editing, and gene therapy. Combined with AI, cryoEM enhances particle identification and 3D structure determination. With recent breakthroughs, cryoEM is emerging as a crucial tool in drug discovery, driving the development of new, effective therapies.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":"1-14"},"PeriodicalIF":6.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947053","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 progress in assay development in leishmaniasis drug discovery: a review of the available papers on PubMed from the past year. 利什曼病药物发现中检测发展的最新进展：去年PubMed现有论文综述。

IF 6 2区医学

Expert Opinion on Drug Discovery Pub Date : 2025-01-06 DOI: 10.1080/17460441.2025.2450787

Gabriela P Dos Santos, Adriano C Coelho, Juliana Q Reimao

{"title":"The latest progress in assay development in leishmaniasis drug discovery: a review of the available papers on PubMed from the past year.","authors":"Gabriela P Dos Santos, Adriano C Coelho, Juliana Q Reimao","doi":"10.1080/17460441.2025.2450787","DOIUrl":"https://doi.org/10.1080/17460441.2025.2450787","url":null,"abstract":"Introduction: Leishmaniasis is a significant neglected tropical disease with limited treatment options that urgently requires ongoing efforts in drug discovery. Recent advances have focused on the development of new assays and methods to identify effective therapeutic candidates.Areas covered: This review explores recent trends and methodologies in leishmaniasis drug discovery, with a particular focus on in silico and in vitro studies, as well as in vivo validation, using animal models. A detailed analysis of recent studies was provided, discussing the methodologies employed, such as manual and automated parasite quantification, and the use of fluorescence and luminescence-based techniques. Additionally, global research trends were analyzed, highlighting the leading countries in scientific output and the collaborative efforts driving advancements in this field.Expert opinion: The field of leishmaniasis drug discovery has rapidly progressed in the last years, but the lack of standardized methodologies and limited in vivo validation remain significant hurdles. To advance promising treatments to clinical trials, cross-validation of preclinical findings and interdisciplinary collaboration are essential. Increased funding and global partnerships are also crucial to accelerate the discovery and development of alternative and effective therapies.","PeriodicalId":12267,"journal":{"name":"Expert Opinion on Drug Discovery","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931066","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