Reviews & Analysis

The Hippo signalling pathway fulfils a vital role in the regulation of tissue homeostasis and organ development and its dysregulation is associated with several diseases. This Review provides an overview of Hippo pathway signalling and regulation, highlighting its biological functions and role in diseases. Recent advances and future directions in the development of Hippo pathway-targeted therapies, primarily in cancer, are discussed.

Tumour cells undergo profound changes in their metabolism, but targeting these metabolic pathways requires understanding of the impact on immune cells as well as cancer cells. This Review discusses how metabolic pathways in cancer and immune cells shape the tumour microenvironment and describes metabolic modulators and dietary nutrients developed to improve the anticancer immune response.

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.

Intrinsically disordered proteins are frequently dysregulated in many diseases, but because of their heterogeneous, highly dynamic structural states they have been considered largely ‘undruggable’ by traditional approaches. This Review proposes that a synergy of advanced experimental and computational approaches will help to overcome this barrier to drug discovery.

The gut microbiome is a key modulator of immunotherapy efficacy. This Review discusses clinical advances in microbiome profiling, recent trials of microbiome-based interventions and the challenges of translating these findings into the clinic. Future directions for optimizing microbiome-targeted therapies in oncology are outlined, including safety, efficacy and patient stratification. 

Neutrophils are abundant in the tumour microenvironment and often correlate with poor prognosis. This Review explores neutrophil subtypes — including those with antitumour activity — their polarization potential and mechanisms influencing tumour progression. Therapeutic targets and signalling pathways are discussed, alongside clinical trials assessing neutrophil-targeted approaches on patient outcomes.

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.

GLP-1-based therapies represent highly effective treatments for patients with type 2 diabetes and obesity. This Review profiles established and emerging GLP-1-based medicines, focusing on novel GLP-1 receptor agonists and GLP-1-based multi-agonists. Considerations and challenges in the development of GLP-1-based therapies and potential future indications are discussed.

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of environmental pollutants and regulates innate and adaptive immune responses. This Review discusses how, in the past, AHR activation was avoided during drug development, but now the AHR is being targeted for treating inflammation, cancer and infectious diseases.

An increasing array of biomarkers available in blood, cerebrospinal fluid and through imaging are providing valuable proxies of disease processes in neurodegenerative disorders (NDDs). In their Review, Cummings and co-authors discuss the implementation of biomarkers in clinical trials across various NDDs, focusing on the context of use, to help expedite and de-risk drug development.

Hundreds of computational resources have been developed that can be applied to repurposing existing drugs for new indications, making it challenging to select the right resource for a specific project. To help address this challenge, this article provides an overview of computational approaches to drug repurposing based on a comprehensive survey of available resources classified into hierarchical categories for a web catalogue, and presents an expert evaluation of selected resources, as well as case studies to illustrate their application.

Fibrosis is a key characteristic of a range of chronic diseases that has been challenging to target with drugs. This Review highlights core pathways active in fibrotic conditions across organs, as well as specific mechanisms and characteristics of fibrotic diseases in the lung, gut, kidney, skin and liver, and provides proposals for strategies to improve the translation of potential antifibrotic therapies.

Multiple tumour-agnostic kinase inhibitors have been approved that are clinically effective regardless of tumour ___location. This Review describes the origins of tumour-agnostic drug development, focusing on small-molecule inhibitors that target kinase pathway aberrations, and discusses the challenges in developing tissue-agnostic agents.

Since its discovery 30 years ago, NRF2 has emerged as a master regulator of cellular homeostasis and has been implicated in a broad range of pathologies. This Review analyses NRF2 regulation, signalling and cross-talk, and assesses the role of this transcription factor in health and disease. The development of therapeutic NRF2 modulators and the associated challenges are also discussed.

G protein-coupled receptors (GPCRs) are one of the largest families of drug targets. This Review analyses drug discovery trends for GPCRs, covering compounds, targets and indications that have reached regulatory approval or that are being investigated in clinical trials, and also highlights the potential of untapped target–disease associations and pathway-biased signalling.

Oncogene MYC has been considered ‘undruggable’ for many decades. This Review provides an overview of the various strategies to inhibit MYC, focusing on the most recently described inhibitors and those that have reached clinical trials.

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.

The family of voltage-gated sodium channels (Na_Vs) are key mediators of electrical signals in excitable cells. In their broad Review, Waxman and colleagues discuss the potential to target Na_Vs in neurons, cardiac and skeletal muscle cells for the treatment of various neurological and muscular disorders.

Immune dysfunction increases with age owing to cellular senescence and low-grade inflammation, processes that drive each other during ageing. This Review discusses the potential of therapeutic approaches that target interactions between the tissue environment and the immune system by eliminating senescent cells, inhibiting inflammation and boosting immune function.

The fibroblast growth factor (FGF) family play critical regulatory roles in development, metabolism and tissue homeostasis and their therapeutic applications are being widely explored. This Review highlights recent advances in understanding of FGF signalling, discusses the current status of endocrine FGF-based drug development and assesses the emerging potential of harnessing paracrine FGFs in the treatment of metabolic diseases.