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Quantitative systems toxicology (QST) models have the potential to increase confidence in the safety assessment of drug candidates and to inform project progression decisions. This article overviews the fundamentals of constructing and using QST models, presents the state-of-the-art for models of cardiovascular, gastrointestinal, hepatic and renal toxicities, and it provides recommendations for their application in drug discovery and development.
Multispecific drugs are designed to engage two or more entities to exert their pharmacological effect. This Perspective discusses how a new wave of FDA-approved multispecific molecules have been transformative in overcoming barriers to drug development such as toxicity, rapid clearance, undruggable protein features, and functional redundancy.
Medicinal chemistry optimizations in the progression from hit to lead to drug candidate affect properties of small-molecule drugs such as their molecular weight and lipophilicity. This Perspective analyses the properties of orally administered small-molecule drug candidates reported in the period 2015–2022 and their corresponding hit and lead compounds, and compares them with the properties of drug candidates identified between 2000 and 2010 and their hits and leads, with the aim of improving understanding of the evolution of hit finding and optimization strategies.
DNA damage to the somatic genome has been identified as a major cause of ageing. This Perspective provides an overview of current understanding of the role of genome instability in the ageing process and assesses therapeutic strategies targeting the cellular response to DNA damage to delay ageing and prevent associated diseases.
New approach methodologies (NAMs) offer the promise of greater predictivity of potential safety risks of drug candidates, especially for newer types of therapeutics for which animal models alone have limited or no applicability for safety testing. This article identifies four categories of drug candidate for which NAMs are applicable and discusses progress in their use based on case studies from recent projects, as well as initiatives to promote the advancement and use of NAMs for more human-relevant safety assessment.
Treatment with chimeric antigen receptor (CAR)-T cell therapies is associated with important immune-related adverse events. In this Review, the authors discuss the standard-of-care management for cytokine release and immune effector cell-associated neurotoxicity syndromes, and the potential of other T cell druggable targets as well as cellular engineering strategies to develop safer CAR-T cells.
