Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review

Targeted protein degradation with proteolysis-targeting chimeras (PROTACs) has the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. This article summarizes the first two decades of PROTAC discovery and discusses key areas for the future of this therapeutic modality, including establishing the target classes for which it is most suitable and extending its application beyond oncology.

Accumulating evidence suggests that, for some people, major depressive disorder has immunological roots. Here, Manji and colleagues discuss the progress towards immune-based treatments for depression, including which biomarkers might be most useful, as well as potential challenges to this approach.

De novo lipogenesis (DNL) is vital for the maintenance of whole-body and cellular homeostasis, but aberrant upregulation of the pathway is associated with a broad range of conditions, including cardiovascular disease, metabolic disorders and cancers. Here, Steinberg and colleagues provide an overview of the physiological and pathological roles of the core DNL enzymes and assess strategies and agents currently in development to therapeutically target them.

This Perspective on cancer immunotherapy marks the tenth anniversary of the approval of the first immune checkpoint blockade (ICB) drug, ipilimumab, revisiting the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.

Despite the link between metabolism and oncogenes, very few metabolism-based drugs for cancer have been successfully developed. This Review covers the setbacks and recent developments in targeting cancer metabolism, and discusses the path forward for the field.

The development of therapies that are capable of safely achieving sizeable and sustained body weight loss has proved tremendously challenging. Here, Müller et al. provide an overview of the history of anti-obesity drug development, focusing on lessons learned, ongoing challenges and recent advances in the field.

Lack of predictive preclinical models is one of the reasons for the high rate of attrition in oncology drug development. This Review discusses the issues in preclinical-to-clinical translatability of molecularly targeted cancer therapies and the need to better align tumour biology in patients with preclinical model systems.

The unfolded protein response (UPR) aims to relieve endoplasmic reticulum (ER) stress and restore protein homeostasis, but also contributes to disease. Here, Marciniak et al. assess small molecules that target ER stress and the UPR, highlighting those diseases in which the role of the UPR and its therapeutic modulation have been most well studied.

The design of cell-based therapeutics with synthetic biology is a rapidly growing strategy in medicine for the development of effective treatments for a variety of diseases. This article discusses advances in synthetic biology approaches to programme living cells with therapeutic functions as well as challenges for their development.

Integrins are key signalling molecules that are present on the surface of subsets of cells and are therefore good potential therapeutic targets. In this Review, Hatley and colleagues discuss the development of integrin inhibitors, particularly the challenges in developing inhibitors for integrins that contain an αv-subunit, and suggest how these challenges could be addressed.

This Review discusses recent findings in transient receptor potential (TRP) channel structural biology and the impact of these findings in drug development and clinical indications. It also addresses the challenges of modulating TRP channels and the need for targeted approaches to minimize potential side-effects due to the multifunctional roles of TRP channels.

The COVID-19 pandemic has established mRNA vaccines as a rapid, effective and safe approach for the protection of individuals from infectious disease. Here, Whitehead and colleagues review the principles of mRNA vaccine design, synthesis and delivery, assessing recent progress and key issues in the development of mRNA vaccines for a range of infectious diseases.

Recent advances in understanding of the complex phenotype and mechanisms underlying atopic dermatitis (AD) have revealed multiple new potential targets for pharmacological intervention. Here, Bieber reviews therapeutic strategies and assesses the expanding pipeline for the therapy of AD, highlighting the potential for a precision medicine approach to the management of this complex disorder.

Diabetes is a substantial and increasing health concern. In this Review, Lickert and colleagues discuss the progress made in developing insulin-producing islets using in vitro methods, including which aspects need to be improved in order to use these islets as transplants. Using these islets in laboratory settings could further our understanding of pancreatic function and the mechanisms underlying diabetes.

The FDA approval of imatinib in 2001 heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. This article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors, their expanding range of indications and strategies for kinase inhibitor design.

In this Review, Weber and Sullivan discuss the different types of immune-related adverse events associated with checkpoint inhibitors and how their treatment may shed light on their mechanisms and possible strategies and targets for prophylactic and therapeutic interventions to mitigate them.

Targeted protein degradation by proteolysis-targeting chimeras (PROTACs) is attracting substantial interest as a therapeutic modality that could circumvent some limitations of traditional small-molecule drugs. This article presents a systematic approach to assessing the PROTAC tractability (PROTACtability) of protein targets, which could support decision-making on whether a particular target may be amenable to modulation using a PROTAC.

Numerous kidney diseases are characterized by a breakdown of the glomerular filtration barrier, which forms the interface between the blood and urine. In this Review, Daehn and Duffield discuss strategies to target components of this barrier, focusing on mechanisms to control mitochondrial function and the actin–myosin machinery, to improve kidney function in individuals with kidney diseases.

A substantial proportion of drug targets are embedded in a cellular membrane, and growing evidence shows that some small molecules access their target via a membrane pathway. Here, Payandeh and Volgraf consider the importance of drug binding at the protein–phospholipid interface, and suggest strategies to harness these concepts for improved drug design.

Although oxidative stress is associated with a broad range of diseases, therapeutic antioxidant approaches have so far been disappointing. Here, Forman and Zhang review the roles of oxidative stress and redox signalling in disease, assess antioxidant therapeutic strategies and highlight key limitations that have challenged their clinical application.