Review, News & Views, Perspectives, Hypotheses and Analyses

Several challenges hamper the translation of preclinical drug discovery efforts into safe and effective therapies for psychiatric disorders. In their Perspective, Khodosevich and colleagues highlight differences between drug targets in animal models and those in patients as a key reason for failed clinical studies. They present a framework that integrates single-cell and spatial omics data to overcome this loss in translation, which they hope will assist the development of new drugs for diseases such as schizophrenia and major depressive disorder.

Advances with deep learning, the growth of databases of molecules for virtual screening and improvements in computational power have supported the emergence of a new field of quantitative structure–activity relationship (QSAR) modelling applications that Tropsha et al. term ‘deep QSAR’. This article discusses key advances in the field, including deep generative and reinforcement learning approaches in molecular design, deep learning models for synthetic planning, and the use of deep QSAR models in structure-based virtual screening.

Current treatments for the two most common chronic inflammatory skin disorders, atopic dermatitis and psoriasis, are mainly limited to the alleviation of symptoms. Here, Bieber discusses opportunities and strategies for the discovery and development of interventions aimed at inducing remission of these disorders and their associated comorbidities, assessing key issues that must be addressed to reach this goal.

The COVID-19 pandemic spurred a wave of rapid and collaborative drug discovery efforts. This Perspective article summarizes scientific drivers and considerations behind such antiviral small-molecule discovery programmes and proposes strategies to accelerate future efforts.

Bivalent protein degraders such as proteolysis targeting chimeras (PROTACs) are entering clinical trials, with a current focus on oral administration. O’Brien Laramy et al. propose that implementing non-oral drug delivery technologies guided by pharmacokinetic–pharmacodynamic modelling could expand the chemical design space for degraders as well as the number of druggable targets.

Bayesian statistical approaches that explicitly incorporate existing data into clinical trial design, analysis and decision-making have the potential to substantially reduce the time and cost of bringing new medicines to patients in some contexts, but remain underused. This Perspective highlights the value of Bayesian methods in drug development, discusses barriers to their application and recommends approaches to address them.

Investigative toxicology tools and strategies are used in pharmaceutical companies to reduce safety-related attrition in drug development. This Perspective article summarizes the key goals of investigative toxicology, highlights current approaches and discusses selected emerging technologies that have the potential to improve the current safety-testing paradigm.

The ‘predictive validity’ of decision tools such as disease models that are used in drug research and development (R&D) — the degree to which the output from a tool correlates with clinical utility in people — has a major influence on R&D productivity. This article explains this influence and discusses methods to evaluate and improve the predictive validity of decision tools, with the aim of supporting the application of more effective tools and catalysing investment in their creation.

Emerging understanding of biomolecular condensates — transient liquid-like droplets made up of proteins and nucleic acids — in normal and aberrant cellular states is providing new insights into human diseases. This Perspective proposes that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics, and discusses the strategies, techniques and challenges involved.

Evidence for a fluid clearance pathway in the central nervous system known as the glymphatic system has grown in the past decade. Nedergaard and colleagues overview the evidence for the glymphatic system and its role in disease, and discuss opportunities to harness the glymphatic system therapeutically; for example, by improving the effectiveness of intrathecally delivered drugs.

This Perspective article discusses the mechanisms used by tumours to evade the immune system, collectively called adaptive immune resistance (AIR), and why defining AIR mechanisms in the tumour microenvironment is key in immunotherapy development.

Phenotypic drug discovery has re-emerged over the past decade as an approach to systematically pursue drug discovery based on therapeutic effects in realistic disease models. This article discusses recent successes with this approach, and considers ongoing challenges and strategies to address them.

Psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have emerging therapeutic potential for neuropsychiatric diseases such as depression and anxiety. In this Perspective, McClure-Begley and Roth discuss the promises and pitfalls of psychedelic pharmacology, including complex activity profiles beyond canonical 5-HT_2A receptor activation that continue to be elucidated. They consider progress and challenges for clinical studies, as well as prospects for parsing the therapeutic from psychedelic effects of this class of compounds to develop ‘cleaner’ drugs.

Many drugs that target amyloid-β in Alzheimer disease have failed in clinical trials. Karran and De Strooper analyse clinical trial data for these drugs in the light of drug properties that could affect their clinical performance. They propose that amyloid plaque would need to be reduced to a low level to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe such a benefit.

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.

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.

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.

Over the past decade, several RNA-based therapies have gained FDA approval. Additional noncoding RNA (ncRNA)-based therapeutic approaches — targeting microRNAs and long ncRNAs — are now also gaining interest. Here, Calin and co-authors assess the hurdles facing the clinical translation of ncRNA-based therapeutics and highlight promising emerging solutions to address these issues.

Physical activity has demonstrated positive effects in preventing and ameliorating a broad range of diseases, particularly central nervous system disorders. Accordingly, strategies to therapeutically mimic the effects of exercise are gaining interest. Here, Gubert and Hannan focus on the molecular and cellular effects of physical activity in the central nervous system, assessing opportunities for the development of therapeutic exercise mimetics.

Despite the rapid growth of the engineered cell therapy sector, there are challenges to the broader industrialization of cells as medicines, especially in the treatment of solid tumours. This Perspective provides an industry perspective on the progress achieved by engineered T cell therapies and discusses strategies to industrialize their potential.