Reviews & Analysis

Advances in areas such as microfluidics-assisted chemical synthesis and biological testing, as well as in artificial intelligence systems, are increasingly providing opportunities to introduce greater automation into the small-molecule drug discovery process. Schneider highlights approaches and technologies that seem poised to be implemented robustly by medicinal chemists in the near future and analyses the challenges for their more widespread application

The contribution of genomics to drug discovery and development so far has not yet lived up to the initial high expectations. Goldstein and colleagues discuss the reasons for the limited progress and review how recent advances — particularly in oncology and rare genetic diseases — may enable precision medicine strategies to harness the therapeutic potential of genomic knowledge.

In this Review, a group of experts in fragile X syndrome analyses why the considerable drug development effort based on robust preclinical findings describing the mechanisms underlying this neurodevelopmental disorder has failed to translate into effective treatment and offers possible solutions to improve clinical trial design and therapeutic approaches.

Understanding the role of enzymes in disease states and the implementation of strategies to modulate their activities for therapeutic benefit remains a key focus for drug discovery. Here, Holdgate and colleagues assess the benefits of conducting and applying high-quality mechanistic enzymology studies throughout a drug-discovery programme and assess the value of combining such knowledge with orthogonal biophysical methods.

Antibody therapeutics are now established as a major drug class. Here, Carter and Lazar comprehensively discuss current and emerging platforms and technologies for antibody therapeutics, with an emphasis on approaches that could extend their therapeutic applications, including antibody–drug conjugates, bispecific antibodies and antibody engineering to enable more effective delivery.

Lysosomal storage disorders (LSDs) are rare, inherited metabolic disorders that result from defects in lysosomal function, for which treatment options are limited. Here, Platt provides an overview of LSDs, approved and potential therapeutic approaches and agents currently in development. The challenges associated with LSD diagnosis, drug development and treatment are discussed.

Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines. Jakinibs — small-molecule inhibitors of JAKs — have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies. This Review discusses the biology, development and efficacy of jakinibs in the treatment of immune and inflammatory diseases.

WD40 repeat (WDR) domain-containing proteins are involved in numerous protein complexes that have been linked to disease. Schapira and colleagues describe recent advances in targeting WDR domains with small molecules to potently inhibit protein–protein interactions, and discuss the potential for the diversity and druggability of WDR domains to open up new pathways for therapeutic intervention.

Aggregates of the microtubule-associated protein tau are a defining feature of several neurodegenerative disorders, including Alzheimer disease (AD). Given the recent failures of several amyloid-β-targeted therapies for AD, interest is growing in tau as an alternative target, and this Review describes preclinical and clinical studies of tau-based approaches in the light of recent advances in the understanding of the physiological and pathological roles of tau.

New therapies for idiopathic pulmonary fibrosis (IPF) are urgently needed. Here, Moraet al. discuss our current understanding of the mechanisms driving IPF, highlighting the parallels between fibrosis and ageing. Potential avenues for drug discovery and development are described, including progress made and current obstacles.

Deubiquitylating enzymes (DUBs) have been implicated in several human diseases, including cancer, neurodegenerative diseases, inflammatory and autoimmune disorders, as well as infectious diseases. Here, Jackson and colleagues discuss the pathological roles of DUBs, consider the challenges in the development of selective DUB inhibitors and highlight first-generation agents approaching clinical trials.

Recent advances in areas such as natural product biosynthesis, synthetic biology and the development of biosensors are providing new opportunities to directly harness evolutionary pressure to identify and optimize compounds with desired bioactivities. This article describes innovations in the key components of such strategies, highlights pioneering examples that indicate their potential, and discusses the scientific gaps and challenges that remain to be addressed to realize this potential more broadly in drug discovery.

Host-directed therapy (HDT) aims to interfere with host cell factors that are required by a pathogen for replication or persistence. In this Review, Kaufmannet al. describe recent progress in the development of HDTs for the treatment of viral and bacterial infections and the challenges in bringing these approaches to the clinic.

Cellular senescence is causally linked to ageing and has been implicated in a variety of age-related diseases. Here, van Deursen and colleagues review the characteristics of senescent cells and highlight evidence for a role of these cells in diseases, including cancer, atherosclerosis and osteoarthritis. Emerging strategies for therapeutically targeting senescent cells and the associated challenges are discussed.

Regeneration of the heart by cardiomyocyte reconstitution represents an attractive approach to treat heart failure. Here, Riley and colleagues discuss recent insights into the biology of heart regeneration and highlight emerging therapeutic regenerative strategies for heart failure. Challenges and considerations in the translation of regenerative therapies into the clinic are discussed.

G protein-coupled receptors (GPCRs) are key drug targets. In this article, Marshall and colleagues discuss the progress made towards generating GPCR-targeting antibodies, including which antigen formats and antibody platforms have been most successful. They review the current pipeline and outline outstanding challenges in antibody generation.

There has been a resurgence in interest in phenotypic drug discovery (PDD) approaches in recent years based on their potential to address the incompletely understood complexity of diseases and their promise of delivering first-in-class drugs. However, PDD approaches can also present considerable challenges, and this article focuses on the lessons learned by researchers engaged in PDD in the pharmaceutical industry, and discusses how PDD can best deliver value to drug discovery portfolios.

Restoring damaged myelin could reverse the neurological effects observed in patients with multiple sclerosis. In this Review, Yong and colleagues discuss the progress made in remyelinating therapies, including novel and potential repurposed agents, and highlight the challenges in preclinical and clinical development for such drugs.

Existing pain therapies are often inadequate or associated with side effects. Here, Woolf and colleagues discuss new and existing strategies for the development of improved pain therapeutics, highlighting key challenges and considerations in the clinical development of novel analgesics.

Dysregulated autophagy is associated with a variety of conditions, including cancer, neurodegenerative diseases, cardiovascular disorders and infectious diseases. However, despite significant efforts, no specific modulators of autophagy have yet been moved into the clinic. Here, Galluzziet al. discuss the therapeutic potential of autophagy modulators and consider the key challenges that have limited their development.