Reviews & Analysis

Image-based profiling is a strategy to mine the rich information in biological images. Carpenter and colleagues discuss how the application of machine learning is renewing interest in image-based profiling for all aspects of the drug discovery process, from understanding disease mechanisms to predicting a drug’s activity or mechanism of action.

Examining B cell depletion therapy (BCDT), an approved treatment for B cell malignancies, in autoimmune conditions has provided key insights into basic B cell biology. In this Review, Gommerman and colleagues discuss BCDT in autoimmune conditions, highlighting diseases in which BCDT has been clinically effective and the potential and pitfalls for BCDT in autoimmune conditions in which it has not yet been efficacious.

The Notch pathway plays multiple complex roles in cancer, exerting oncogenic or tumour-suppressive actions depending on the context. Here Miele and colleagues provide an overview of current understanding of the functions of Notch in cancer, highlighting key implications for the development of Notch-targeting therapeutics. Agents in clinical development and emerging therapeutic strategies are highlighted.

Advances in nanoparticle design could make substantial contributions to personalized and non-personalized medicine. In this Review, Langer, Mitchell, Peppas and colleagues discuss advances in nanoparticle design that overcome heterogeneous barriers to delivery, as well as the challenges in translating these design improvements into personalized medicine approaches.

Academic research has a key role in identifying new drug targets, but to lead to new drugs this research must progress to testing drug candidates in clinical trials, which are typically conducted by industry. This Perspective presents a framework to support academic scientists and funders in prioritizing target assessment activities and in defining a critical path to reach scientific goals as well as goals related to licensing, partnering with industry or initiating clinical trials.

Targeting protein complexes, including those containing G protein-coupled receptors or ligand-gated ion channels, could provide opportunities to increase the target and functional selectivity of novel drugs compared with existing therapies, which only target the receptors. This Review discusses the landscape of ligand-gated ion channel and G protein-coupled receptor complexes as therapeutic targets, as well as strategies for their pharmacological modulation.

FOXO proteins are transcription factors that regulate responses to stress stimuli to maintain cellular homeostasis. The deregulation of FOXO protein functions plays a role in cardiovascular disease, cancer, diabetes and neurological diseases. This Review summarizes the biology of FOXO proteins and their functions in disease and longevity and discusses the pharmacological approaches to develop FOXO-targeting therapeutics.

Base editing is emerging as a potential approach to treat genetic diseases through the introduction of single-nucleotide alterations in DNA and RNA. Here, Porto et al. provide an overview of DNA and RNA base editing, discuss recent advances in the development of these technologies and highlight promising therapeutic applications.

Unmet medical needs in the treatment of autoimmune and inflammatory diseases still exist. This Review discusses the activity of kinases that regulate production of inflammatory mediators and the recent advances in developing inhibitors to target such kinases.

cis-Regulation therapy (CRT) — modifying the activity of gene-regulatory elements — is emerging as a potential approach to treat genetic diseases. Here, Matharu and Ahituv assess emerging CRT technologies and present proof-of-concept studies in cell and animal models. Key factors to be considered for the translation of CRT into the clinic are discussed.

Immune activating antibodies that target co-stimulatory molecules have altered the cancer therapy landscape. Here, Walker and colleagues discuss therapies — particularly those that target molecules in the same families as CTLA4 and PD1 or TNF receptor — that inhibit the immune system and are being investigated for the treatment of autoimmune diseases. They describe the future opportunities and challenges for the field, including combination approaches.

Aberrant epigenetic processes can influence tumour immunogenicity and immune cells involved in the response to cancer. This Review highlights how epigenetic regulators can be modulated with small-molecule drugs to promote antitumour immune responses, and discusses the opportunities and challenges for developing cancer treatment regimens that combine epigenetic therapies with immunotherapies.

Organs-on-chips (OoCs) could be useful at various stages of drug discovery and development, providing insight regarding human organ physiology in both normal and disease contexts, as well as accurately predicting developmental drug safety and efficacy. This Review discusses the advances that have enabled OoCs to demonstrate physiological relevance, and the challenges and opportunities that need to be tackled to tap the full potential of OoC utility for translational research.

Phase 0 approaches, including microdosing, evaluate subtherapeutic exposures to novel drugs, potentially enabling safer, cheaper and quicker first-in-human studies. Here, Burt et al. discuss the fundamentals and applications of phase 0 approaches, highlight the potential advantages of their application in drug development and address the associated limitations.

Several poly(ADP-ribose) polymerase (PARP) inhibitors have now been approved as treatments for various types of cancer. In this Review, Curtin and Szabo discuss the history of the development of PARP inhibitors and progress in their use for cancer therapy, as well as the potential for repurposing PARP inhibitors for the treatment of non-oncological diseases such as stroke.

With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.

Oligonucleotide-based drugs have the potential to treat or manage a wide range of diseases. However, the widespread application of such therapies has been hampered by the difficulty in achieving efficient delivery to extrahepatic tissues. Here, Roberts et al. overview oligonucleotide-based drug platforms and assess approaches being employed to improve their delivery.

Dendritic cell vaccines have been widely investigated as a type of cancer immunotherapy, but their promise has not yet been realized. Kandalaft and colleagues propose that a prime and boost approach — primed with either standard therapies or dendritic cell vaccines and boosted with a personalized synthetic vaccine — could help fulfil the potential of such vaccines. They discuss improvements in dendritic cell vaccines that have enabled prime–boost approaches, as well as challenges for adoption.

Radiopharmaceutical therapy is emerging as a safe and effective approach for the treatment of cancer, offering several advantages over existing therapeutic strategies. Here, Sgouros and colleagues provide an overview of the fundamental properties of radiopharmaceutical therapy, discuss agents in use and in clinical development and highlight the associated translational challenges.

Accumulating evidence indicates that impaired glucose metabolism in the brain is involved in the cause and progression of neurodegenerative disorders of ageing such as Alzheimer disease. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by rescuing, protecting or normalizing brain energetics.