Drug Discovery Today最新文献

Chronic lymphocytic leukemia (CLL), a malignant tumour, is characterized by expansion of mature monoclonal B lymphocytes expressing CD23 and CD5 in secondary lymphocytic organs, blood, and bone marrow. Here, we provide an in-depth review of CLL, emphasizing its pathophysiology, cytogenic changes, and treatment strategies, particularly the efficacy and challenges of treatments, such as Bruton tyrosine kinase (BTK) inhibitors, B cell lymphoma 2 (BCL2) inhibitors, and phosphatidylinositol 3-kinase (PI3K) inhibitors, as well as the need to understand their role in managing disease progression, chemoresistance, and intolerance. In addition, we explore efficacy based on patient response and comparison between monotherapy and combination therapy. We also highlight the need for innovative strategies to overcome treatment resistance and enhance patient outcomes.

Artificial intelligence-driven drug discovery (AIDD) companies hold significant promise for transforming pharmaceutical development, yet little is known about how they manage partnerships with established pharmaceutical firms. To address this research gap, our study explores how AIDD companies develop and leverage relational capabilities to enhance collaboration effectiveness. Through a case study approach, we focus on four key relational aspects: identifying complementary capabilities, establishing effective governance mechanisms, creating relationship-specific assets, and developing interfirm knowledge-sharing routines. Our findings demonstrate that particularly effective governance of intellectual property is essential for partnership success. We offer actionable recommendations for AIDD companies to strengthen collaborations, thereby contributing to the realization of AI's potential in drug discovery.

China has initiated drug regulatory reforms since 2015. Here, we analyze the characteristics and trends of domestic innovative drugs approved for marketing in China from January 2010 to May 2024 to explore the effectiveness of drug regulatory reform. Overall, 219 drugs were approved, with growth in chemicals and therapeutic biologics post-reform. Single-arm trials as an important option for clinical trial design of antineoplastic agents increased. The time for each link from investigational new drug (IND) to new drug application (NDA) has been shortened post-reform. Moreover, the time for access to medical insurance for approved drugs has been shortened and price reductions have been increased. China's drug regulatory reforms have made progress in improving the accessibility of domestic innovative drugs.

The concept of a 'magic bullet' was first introduced by Paul Ehrlich in the early 1900s, he foresaw the advent of targeted therapies and the specific killing of harmful cells and/or microorganisms. However, these therapies were only used in the clinic after the second half of the 20th century with the development of specific monoclonal antibodies. To date, 13 antibody-drug conjugates (ADCs) are commercially available. Many advances have been made by modifying one or several of the three main components of an ADC, namely the antibody, the cleavable or non-cleavable linker or the payload, and by integrating conjugation chemistry. Despite these efforts, some problems have emerged and thus limit their effectiveness. New strategies could overcome these problems and identify the next generation of ADC.

This article presents a comprehensive examination of processes related to the prediction of human pharmacokinetics (PK), a crucial task of clinical drug candidate selection. By systematically incorporating in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo PK data with expert judgement, the study achieves high-quality human PK predictions for 40 orally administered compounds from Boehringer Ingelheim's new chemical entity (NCE) portfolio. Overall, the article provides a detailed evaluation of and guidance for a structured process to predict full concentration-time profiles beyond single-parameter predictions, using state-of-the-art methodologies. Furthermore, it discusses future challenges and improvements, and aims to provide valuable insights for scientists working in drug metabolism, PK and pharmacodynamics.

Autophagy, the lysosome-driven breakdown of intracellular components, is pivotal in regulating eukaryotic cellular processes and maintaining homeostasis, making it physiologically important even under normal conditions. Cellular mechanisms that involve autophagy include the starvation response, intracellular quality control, early development, and cell differentiation. Despite its established health significance, the role of autophagy in cancer and other diseases is unclear. It is important to understand this mechanism thoroughly so that innovative therapies against various diseases can be designed and implemented and so that drugs can be developed to protect human health. High-throughput technologies have allowed researchers to study transcriptional landscapes at single-cell resolution, improving our understanding of autophagy pathways in various physiological and pathological conditions. This paper discusses single-cell RNA sequencing advances in autophagy research and the molecular characterization of multiple diseases.

The promise of curative outcomes for life-limiting diseases using cell therapies is starting to become a reality, not only for patients with end-stage cancer, but also increasingly for regenerative therapies, including dentistry, ocular, neurodegenerative, and cardiac diseases. The introduction of often genetically modified cells into a patient can come with an extensive range of safety considerations. From an immune perspective, cell-based therapies carry inherent consequences and consideration of factors, such as the cell source (donor-derived autologous cells versus allogeneic cells), the intrinsic cellular nature of the therapy, and engineering/manufacturing methods, all of which influence the likelihood of inducing unwanted immune responses. Here, we provide an overview of the potential immune safety risks associated with cell therapies and explore possible mitigation approaches.

Multicomponent reactions (MCRs) have significant relevance in the field of synthetic chemistry, and in recent times one of the MCR variants, named the Groebke-Blackburn-Bienaymé (GBB) reaction, has attracted massive attention for the synthesis of biologically important scaffolds. The present review elaborates on the chemical advancement reported for the GBB reaction with an emphasis on the role of various catalytic systems. Further, the role of the GBB reaction has been redefined as a standard protocol for the synthesis of an array of potential bioactive compounds.

This study presents a comprehensive analysis of the global bioequivalence (BE) trial landscape over the past 21 years, utilizing data from the Trialtrove database. We analyzed 12,450 BE trials conducted from 2003 to 2023, revealing a significant upward trend in trial numbers. Among the analysis, the primary therapeutic areas identified were cardiovascular diseases (23.17%) and metabolic/endocrinology conditions (18.91%). China leads in BE trials, accounting for 57.20% of the total, followed by Russia and the United States. Most trials are sponsored by the industry, predominantly by generic pharmaceutical companies. This study highlights the importance of diverse representation in trial populations to enhance the validity of results. We discuss strategies for improving trial success rates, including preliminary trials and in vitro dissolution testing. Furthermore, the need for international harmonization of generic drug standards is emphasized, along with the potential impact of advanced technologies, such as artificial intelligence, on future BE research.

This paper describes the theory of evolutionary economics in the context of pharmaceutical R&D. In this context, the R&D productivity crisis acts as a key selection mechanism, and R&D, technology and industry trends provide mechanisms of variation. Drawing on today's prevailing business model among leading pharmaceutical companies, the biotech-leveraged pharma company (BIPCO), I propose two new value creation logics: the technology-investigating pharma company (TIPCO) and the asset-integrating pharma company (AIPCO). Although some companies already share aspects of these business models, it is not yet clear, in terms of evolutionary economics, what the ultimate outcome of the evolutionary process in pharma R&D will be.