Expert Opinion on Drug Discovery最新文献

Introduction: Hidradenitis suppurativa (HS) is a chronic skin condition with a significant impact on patient quality of life, highlighting the need for innovative therapeutic approaches. HS is characterized by its chronicity; it presents in the form of painful nodules, abscesses, and sinus tracts or fistulas, typically localized in intertriginous areas, emerging in early adulthood and in predominantly the female population.

Areas covered: In this review, the authors discuss the preclinical discovery and development of secukinumab for HS, highlighting target identification, validation, and compound selection. Methodologies such as high-content screening, chemoinformatics, and animal models that validate the IL-17 pathway's role in HS are explored. The transition from preclinical to clinical development, including pharmacokinetics (PK), pharmacodynamics (PD), and ADME-Tox studies, is elaborated. The literature search was conducted using PubMed, Web of Science, Scopus, UpToDate, Cochrane Library, Embase, and Google Scholar, covering relevant studies published up to December 2024.

Expert opinion: The integration of secukinumab into HS treatment highlights the critical role of targeting the IL-17A pathway. Although efficacious and safe in trials, understanding secukinumab's long-term effects and optimal treatment placement remains challenging. Future research should prioritize the development of tailored therapeutic strategies that align with individual disease phenotypes and immune profiles to enhance treatment outcomes in HS management.

Introduction: Erectile dysfunction (ED) is a common condition that often signals underlying endothelial dysfunction, although the underlying causative factor(s) are likely complex and multifactorial. Various animal models have been developed to provide a research platform to study ED and served as an important basis for the discovery and subsequent development of novel therapeutic drugs for ED.

Areas covered: The review article provides an overview of various animal models in ED research with an emphasis on important drug target discovery relating to each specific experimental model. The authors highlight translation from basic science research to major preclinical and clinical studies in this evolving field of ED research.

Expert opinion: Animal models simulate the pathological features of various types of ED and clarify their molecular mechanisms. These mechanisms aid in discovering drug targets, while established ED models also provide a basis for validating drug efficacy, safety, and specific action mechanisms. The development of techniques in detection methods, cellular experimental, and omics has a profound impact on disease prediction, model evaluation, and optimization of therapeutic modalities. On this basis, many drug therapies targeting these ED-related mechanisms, especially in the nitric oxide/cyclic guanosine monophosphate pathways have been applied in preclinical studies. However, focusing on drug development for those types of ED where phosphodiesterase 5 inhibitor therapy is limited may be more valuable.

Introduction: Aurora kinases (AKs) play key roles during carcinogenesis and show a close relationship with many cellular effects including mitotic entry, spindle assembly and chromosomal alignment biorientation. Indeed, elevated levels of AKs have been reported in several different tumor types, leading research scientists to investigate ways that we can target AKs for the purpose of developing new anticancer therapeutics.

Area covered: This review examines the design, discovery, and development of Aurora kinase inhibitors (AKIs) as anticancer agents and delineates their roles in cancer progression or development. Various databases like PubMed, Scopus, Google scholar, SciFinder were used to search the relevant information. This article provides a comprehensive overview of recent advances in the medicinal chemistry of AKIs including the candidates under clinical development and list of patents filed. In addition, their mechanistic findings, SARs, and in silico studies have also been discussed to offer prospects in this field.

Expert opinion: The integration of artificial intelligence and computational approaches is poised to accelerate the development of AKIs as anticancer agents. However, the associated challenges currently hindering its impact in drug development must be overcome before drugs can successfully translate from early drug development into clinical practice.

Introduction: Androgenetic alopecia (AGA) is the most common cause of hair loss worldwide. The significant psychological and social impact of AGA continues to drive demand for more effective treatments beyond the limited options currently available.

Areas covered: The authors review the key components of AGA pathogenesis, as well as current treatments, and therapeutic techniques under development. Innovative strategies for AGA drug discovery are still needed, given the significant unmet medical needs and the limited efficacy of both current and emerging treatments. The authors outline relevant preclinical models, such as hair follicle (HF) cell cultures, 3D spheroids, organoids, follicle explants, and animal models, highlighting their advantages and limitations in AGA research. Finally, they summarize the primary objectives in AGA treatment development, including direct hair growth promotion, interference with androgen signaling, and HF rejuvenation, identifying key pathogenesis intervention points for treatment development.

Expert opinion: Developing better in vitro models, possibly using induced pluripotent stem cell (iPSC) systems, could greatly accelerate drug discovery. Similarly, a superior in vivo model could significantly expedite drug discovery. Near future development research should focus on drug delivery improvements. Longer term, treatments targeting AGA's underlying pathophysiology and promoting HF rejuvenation or true regeneration would provide the most benefit to prospective patients.

Introduction: Snake venom is a rich source of toxins with great potential for therapeutic applications. In addition to its efficacy in treating hypertension, acute coronary syndrome, and other heart conditions, research has shown that this potent enzymatic cocktail is capable of selectively targeting and destroying cancer cells in many cases while sparing healthy cells.

Areas covered: The authors begin by acknowledging the emerging trends in snake-derived targeted therapies in battling cancer. An extensive literature review examining the effects of various snake venom toxins on cancer cell lines, highlighting the specific cancer hallmarks each toxin targets is presented. Furthermore, the authors emphasize the emerging potential of artificial intelligence in accelerating snake venom-based drug discovery for cancer treatment, showcasing several innovative software applications in this field.

Expert opinion: Research on snake venom toxins indicates promising potential for cancer treatment as many of the discussed toxins can specifically target cancer cells. Nevertheless, variations in the composition of venoms, ethical issues, and delivery barriers limit their development into effective therapies. Thus, advances in biotechnology, molecular engineering, in silico methods are crucial for the refinement of venom-derived compounds, improving their specificity, and overcoming these challenges, ultimately enhancing their therapeutic potential in cancer therapy.

Introduction: The use of laboratory animals is essential to understand the mechanisms underlying COPD and to discover and evaluate new drugs. However, the complex changes associated with the disease in humans are difficult to fully replicate in animal models.

Areas covered: This review examines the most recent literature on animal models of COPD and their implications for drug discovery and development.

Expert opinion: Recent advances in animal models include the introduction of transgenic mice with an increased propensity to develop COPD-associated features, such as emphysema, and animals exposed to relevant environmental agents other than cigarette smoke, in particular biomass smoke and other air pollutants. Other animal species, including zebrafish, pigs, ferrets and non-human primates, are also increasingly being used to gain insights into human COPD. Furthermore, three-dimensional organoids and humanized mouse models are emerging as technologies for evaluating novel therapeutics in more human-like models. However, despite these advances, no model has yet fully captured the heterogeneity and progression of COPD as observed in humans. Therefore, further research is needed to develop improved models incorporating humanized elements in experimental animals, that may better predict therapeutic responses in clinic settings and accelerate the development of new treatments for this debilitating disease.

Introduction: In 2023, the first exascale supercomputer was opened to the public in the US. With a demonstrated 1.1 exaflops of performance, Frontier represents an unprecedented breakthrough in high-performance computing (HPC). Currently, more (and more powerful) machines are being installed worldwide. Computer-aided drug design (CADD) is one of the fields of computational science that can greatly benefit from exascale computing for the benefit of the whole society. However, scaling CADD approaches to exploit exascale machines require new algorithmic and software solutions.

Areas covered: Here, the authors consider physics-based and machine learning (ML)-aided techniques for the design of small molecule binders capable of leveraging modern parallel computer architectures. Specifically, the authors focus on HPC-oriented large-scale applications from the past 3 years that were enabled by (pre)exascale supercomputers by running on up tothousands of accelerated nodes.

Expert opinion: In the area of ML, exascale computers can enable the training of generative models with unprecedented predictive power to design novel ligands, provided large amounts of high-quality data are available. Exascale computers could also unlock the potential of accurate ML-aided physics-based methods to boost the success rate of structure-based drug design campaigns. Currently, however, methodological developments are still required to allow routine large-scale applications of such rigorous approaches.

Introduction: China's pharmaceutical industry, which is historically centered around generic medicines, has largely transformed from imitation to innovation over the past three decades. Despite unprecedented progress, critical challenges remain such as insufficient indigenous research funding, underdeveloped academia-industry relationships, and significant barriers to market access.

Areas covered: This perspective examines the evolving pharmaceutical landscape of China, focusing on its participation in global clinical trials and the resultant new drug approvals. Data for this analysis was sourced from several databases (e.g. PharmCube, NextPharma, and PharmaGO), academic reports, and published literature, covering data up to 2024 (unless otherwise specified). This perspective highlights ongoing regulatory challenges, such as inconsistencies in product standards, and the approval processes relative to the U.S.A. and the European Union. There is also an urgent demand for sustained international investment and recognition, partially due to the recent changes in the geopolitical environment. This perspective also discusses China's efforts to implement accelerated approval pathways and foster multilateral development collaborations.

Expert opinion: China must align its regulatory policies more closely to the international norm to generate robust trial data that will be readily acceptable to the FDA and EMA. Continued investment in biologics as well as cell and gene therapy and artificial intelligence will drive innovation and enhance competitiveness. Additionally, strengthening the academia-industry collaboration is crucial to obtaining new leads through translational research. Ultimately, structural reforms are required to solidify the country's goal of becoming a major player in the global pharmaceutical market.

Introduction: Bladder cancer presents a significant health problem worldwide, with environmental and genetic factors contributing to its incidence. Histologically, it can be classified as carcinoma in situ, non-muscle invasive and muscle-invasive carcinoma, each one with distinct genetic alterations impacting prognosis and response to therapy. While traditional transurethral resection is commonly performed in carcinoma in situ and non-muscle invasive carcinoma, it often fails to prevent recurrence or progression to more aggressive phenotypes, leading to the frequent need for additional treatment such as intravesical chemotherapy or immunotherapy. Despite the advances made in recent years, treatment options for bladder cancer are still lacking due to the complex nature of this disease. So, animal models may hold potential for addressing these limitations, because they not only allow the study of disease progression but also the evaluation of therapies and the investigation of drug repositioning.

Areas covered: This review discusses the use of animal models over the past decade, highlighting key discoveries and discussing advantages and disadvantages for new drug discovery.

Expert opinion: Over the past decade animal models have been employed to evaluate new mechanisms underlying the responses to standard therapies, aiming to optimize bladder cancer treatment. The authors propose that molecular engineering techniques and AI may hold promise for the future development of more precise and effective targeted therapies in bladder cancer.