Drug Discovery Today最新文献

Characterization analysis of 87 pivotal clinical trials for 72 novel orphan drugs (76 orphan indications) approved by the FDA from 2017 to 2023 revealed that the clinical trial evidence supporting FDA orphan drug approvals often lacked high-quality designs, which frequently did not incorporate randomization, blinding, placebo or no treatment control, or clinical endpoint-driven methodologies. Additionally, regulatory flexibility was observed in the quantity of clinical trial evidence required, which included choices such as a single trial plus confirmatory evidence, one large multicenter trial or at least two trials. Furthermore, the overall strength of the clinical trial evidence exhibited variations across different orphan drugs and indications, influenced by features such as the therapeutic area and whether the orphan drug was granted accelerated approvals.

The discipline of structure-based drug design (SBDD) is several decades old and it is tempting to think that the proliferation of experimental structures for many drug targets might make computer-aided drug design (CADD) straightforward. However, this is far from true. In this review, we illustrate some of the challenges that CADD scientists face every day in their work, even now. We use Rho-associated protein kinase (ROCK), and public domain structures and data, as an example to illustrate some of the challenges we have experienced during our project targeting this protein. We hope that this will help to prevent unrealistic expectations of what CADD can accomplish and to educate non-CADD scientists regarding the challenges still facing their CADD colleagues.

Cancer, a multifaceted and pernicious disease, continuously challenges medicine, requiring innovative treatments. Brain cancers pose unique and daunting challenges due to the intricacies of the central nervous system and the blood–brain barrier. In this era of precision medicine, the convergence of neurology, oncology, and cutting-edge technology has given birth to a promising avenue – targeted cancer therapy. Furthermore, bioinspired microrobots have emerged as an ingenious approach to drug delivery, enabling precision and control in cancer treatment. This Keynote review explores the intricate web of neurological insights into brain-targeted cancer therapy and the paradigm-shifting world of bioinspired microrobots. It serves as a critical and comprehensive overview of these evolving fields, aiming to underscore their integration and potential for revolutionary cancer treatments.

This review focuses on the advancements in manganese (Mn) complex-based magnetic resonance imaging (MRI) agents for imaging different diseases. Here we emphasize the unique redox properties of Mn to deliver innovative MRI contrast agents, including small molecules, nanoparticles (NPs), metal–organic frameworks (MOFs), and polymer hybrids. Aspects of their rational design have been discussed, including size dependence, morphology tuning, surface property enhancement, etc., while also discussing the existing challenges and potential solutions. The present work will inspire and motivate scientists to emphasize MRI-guided applications and bring clinical success in the coming years.

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure–activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.

Efforts to accelerate Alzheimer’s disease (AD) drug development have been spurred on by the creation of open science, public–private R&D consortia. An R&D consortium provides an improved structure for generating and disseminating AD knowledge across a range of organizations while also aligning their interests. Drawing from archival and interview data collected on 46 public–private R&D consortia focused wholly or in part on AD, we uncover two important innovations: the creation of novel consortium types that facilitate coordination beyond the individual consortium, and the practice of organizations joining multiple consortia. Collectively these innovations provide member organizations with different pathways for advancing AD research. These findings have significant implications for how member organizations should approach collaboration in the AD drug development process.

Histone deacetylases (HDACs) are a special class of hydrolase enzymes, which through epigenetic control of cellular acetylation, play regulatory roles in various processes including chromatin packing, cytokine signaling, and gene expression. Widespread influence on cell function has implicated dysregulated HDAC activity in human disease. While traditionally an oncology target, in the past decade, there has been a notable rise in inhibition strategies within several therapeutic areas beyond cancer. This review highlights advances in four of these indications, neurodegenerative disease, metabolic disorders, cardiovascular disease, and viral infections, focusing on the role of deacetylases in disease, small molecule drug discovery, and clinical progress.

Block copolymer micelles, formed by the self-assembly of amphiphilic polymers, address formulation challenges, such as poor drug solubility and permeability. These micelles offer advantages including a smaller size, easier preparation, sterilization, and superior solubilization, compared with other nanocarriers. Preclinical studies have shown promising results, advancing them toward clinical trials. Their mucoadhesive properties enhance and prolong contact with the ocular surface, and their small size allows deeper penetration through tissues, such as the cornea. Additionally, copolymeric micelles improve the solubility and stability of hydrophobic drugs, sustain drug release, and allow for surface modifications to enhance biocompatibility. Despite these benefits, long-term stability remains a challenge. In this review, we highlight the preclinical performance, structural frameworks, preparation techniques, physicochemical properties, current developments, and prospects of block copolymer micelles as ocular drug delivery systems.

As the global population ages, the need to prolong lifespan and healthspan becomes increasingly imperative. Understanding the molecular determinants underlying cognitive resilience, together with changes during aging and the (epi)genetic factors that predispose an individual to decreased cognitive resilience, open avenues for researching novel therapies. This review provides a critical and timely appraisal of the molecular mechanisms underlying cognitive resilience, framed within a critical analysis of emerging therapeutic strategies to mitigate age-related cognitive decline. Significant insights from both animals and human subjects are discussed herein, directed either toward active pharmaceutical ingredients (drug repositioning or macromolecules), or, alternatively, advanced cellular therapies.