Showing papers in "Nature Reviews Drug Discovery in 2018"

mRNA vaccines — a new era in vaccinology

Abstract: mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

Targeting macrophages: therapeutic approaches in cancer.

Abstract: Infiltration of macrophages in solid tumours is associated with poor prognosis and correlates with chemotherapy resistance in most cancers. In mouse models of cancer, macrophages promote cancer initiation and malignant progression by stimulating angiogenesis, increasing tumour cell migration, invasion and intravasation and suppressing antitumour immunity. At metastatic sites, macrophages promote tumour cell extravasation, survival and subsequent growth. Each of these pro-tumoural activities is promoted by a subpopulation of macrophages that express canonical markers but have unique transcriptional profiles, which makes tumour-associated macrophages (TAMs) good targets for anticancer therapy in humans through either their ablation or their re-differentiation away from pro-tumoural towards antitumoural states. In this Review, we evaluate the state of the art of TAM-targeting strategies, focusing on the limitations and potential side effects of the different therapies such as toxicity, rebound effects and compensatory mechanisms. We provide an extensive overview of the different types of therapy used in the clinic and their limitations in light of known macrophage biology and propose new strategies for targeting TAMs.

Targeting the NLRP3 inflammasome in inflammatory diseases

Abstract: Danger signals are a hallmark of many common inflammatory diseases, and these stimuli can function to activate the cytosolic innate immune signalling receptor NLRP3 (NOD-, LRR- and pyrin domain-containing 3). Once activated, NLRP3 nucleates the assembly of an inflammasome, leading to caspase 1-mediated proteolytic activation of the interleukin-1β (IL-1β) family of cytokines, and induces an inflammatory, pyroptotic cell death. Pharmacological inhibition of NLRP3 activation results in potent therapeutic effects in a wide variety of rodent models of inflammatory diseases, effects that are mirrored by genetic ablation of NLRP3. Although these findings highlight the potential of NLRP3 as a drug target, an understanding of NLRP3 structure and activation mechanisms is incomplete, which has hampered the discovery and development of novel therapeutics against this target. Here, we review recent advances in our understanding of NLRP3 activation and regulation, highlight the evolving landscape of NLRP3 modulators and discuss opportunities for pharmacologically targeting NLRP3 with novel small molecules.

Kinase inhibitors: the road ahead

Abstract: Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.

Next generation antibody drugs: pursuit of the 'high-hanging fruit'.

Abstract: 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.

Biased signalling: from simple switches to allosteric microprocessors

Abstract: A given G protein-coupled receptor can signal through a range of downstream transducers depending on the stimulating ligand, enabling biased signalling towards different biological outcomes. Lefkowitz and colleagues describe the latest advances in the field, including efforts to harness biased signalling for improved therapeutic outcomes. G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR kinases and β-arrestins. While these signalling pathways can be activated or blocked by 'balanced' agonists or antagonists, they can also be selectively activated in a 'biased' response. Biased responses can be induced by biased ligands, biased receptors or system bias, any of which can result in preferential signalling through G proteins or β-arrestins. At many GPCRs, signalling events mediated by G proteins and β-arrestins have been shown to have distinct biochemical and physiological actions from one another, and an accurate evaluation of biased signalling from pharmacology through physiology is crucial for preclinical drug development. Recent structural studies have provided snapshots of GPCR–transducer complexes, which should aid in the structure-based design of novel biased therapies. Our understanding of GPCRs has evolved from that of two-state, on-and-off switches to that of multistate allosteric microprocessors, in which biased ligands transmit distinct structural information that is processed into distinct biological outputs. The development of biased ligands as therapeutics heralds an era of increased drug efficacy with reduced drug side effects.

Deubiquitylating enzymes and drug discovery: emerging opportunities.

Abstract: More than a decade after a Nobel Prize was awarded for the discovery of the ubiquitin-proteasome system and clinical approval of proteasome and ubiquitin E3 ligase inhibitors, first-generation deubiquitylating enzyme (DUB) inhibitors are now approaching clinical trials However, although our knowledge of the physiological and pathophysiological roles of DUBs has evolved tremendously, the clinical development of selective DUB inhibitors has been challenging In this Review, we discuss these issues and highlight recent advances in our understanding of DUB enzymology and biology as well as technological improvements that have contributed to the current interest in DUBs as therapeutic targets in diseases ranging from oncology to neurodegeneration

Mitochondria as a therapeutic target for common pathologies.

Abstract: Although the development of mitochondrial therapies has largely focused on diseases caused by mutations in mitochondrial DNA or in nuclear genes encoding mitochondrial proteins, it has been found that mitochondrial dysfunction also contributes to the pathology of many common disorders, including neurodegeneration, metabolic disease, heart failure, ischaemia-reperfusion injury and protozoal infections. Mitochondria therefore represent an important drug target for these highly prevalent diseases. Several strategies aimed at therapeutically restoring mitochondrial function are emerging, and a small number of agents have entered clinical trials. This Review discusses the opportunities and challenges faced for the further development of mitochondrial pharmacology for common pathologies.

Host-directed therapies for bacterial and viral infections

Abstract: Despite the recent increase in the development of antivirals and antibiotics, antimicrobial resistance and the lack of broad-spectrum virus-targeting drugs are still important issues and additional alternative approaches to treat infectious diseases are urgently needed Host-directed therapy (HDT) is an emerging approach in the field of anti-infectives The strategy behind HDT is to interfere with host cell factors that are required by a pathogen for replication or persistence, to enhance protective immune responses against a pathogen, to reduce exacerbated inflammation and to balance immune reactivity at sites of pathology Although HDTs encompassing interferons are well established for the treatment of chronic viral hepatitis, novel strategies aimed at the functional cure of persistent viral infections and the development of broad-spectrum antivirals against emerging viruses seem to be crucial In chronic bacterial infections, such as tuberculosis, HDT strategies aim to enhance the antimicrobial activities of phagocytes and to curtail inflammation through interference with soluble factors (such as eicosanoids and cytokines) or cellular factors (such as co-stimulatory molecules) This Review describes current progress in the development of HDTs for viral and bacterial infections, including sepsis, and the challenges in bringing these new approaches to the clinic

The expanding role of prodrugs in contemporary drug design and development

Abstract: Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting. In the past 10 years, the US Food and Drug Administration has approved at least 30 prodrugs, which accounts for more than 12% of all approved small-molecule new chemical entities. In this Review, we highlight prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs. We also discuss preclinical and clinical challenges and considerations in prodrug design and development.

Automating drug discovery

Abstract: Small-molecule drug discovery can be viewed as a challenging multidimensional problem in which various characteristics of compounds - including efficacy, pharmacokinetics and safety - need to be optimized in parallel to provide drug candidates. Recent advances in areas such as microfluidics-assisted chemical synthesis and biological testing, as well as artificial intelligence systems that improve a design hypothesis through feedback analysis, are now providing a basis for the introduction of greater automation into aspects of this process. This could potentially accelerate time frames for compound discovery and optimization and enable more effective searches of chemical space. However, such approaches also raise considerable conceptual, technical and organizational challenges, as well as scepticism about the current hype around them. This article aims to identify the approaches and technologies that could be implemented robustly by medicinal chemists in the near future and to critically analyse the opportunities and challenges for their more widespread application.

Interleukin-6: designing specific therapeutics for a complex cytokine

Abstract: Interleukin-6 (IL-6) is a pivotal cytokine with a diverse repertoire of physiological functions that include regulation of immune cell proliferation and differentiation. Dysregulation of IL-6 signalling is associated with inflammatory and lymphoproliferative disorders such as rheumatoid arthritis and Castleman disease, and several classes of therapeutics have been developed that target components of the IL-6 signalling pathway. So far, monoclonal antibodies against IL-6 or IL-6 receptor (IL-6R) and Janus kinases (JAK) inhibitors have been successfully developed for the treatment of autoimmune diseases such as rheumatoid arthritis. However, clinical trials of agents targeting IL-6 signalling have also raised questions about the diseases and patient populations for which such agents have an appropriate benefit-risk profile. Knowledge from clinical trials and advances in our understanding of the complexities of IL-6 signalling, including the potential to target an IL-6 trans-signalling pathway, are now indicating novel opportunities for therapeutic intervention. In this Review, we overview the roles of IL-6 in health and disease and analyse progress with several approaches of inhibiting IL-6-signalling, with the aim of illuminating when and how to apply IL-6 blockade.

Principles for targeting RNA with drug-like small molecules

Abstract: RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these RNAs with small molecules offers opportunities to therapeutically modulate numerous cellular processes, including those linked to 'undruggable' protein targets. Despite this promise, there is currently only a single class of human-designed small molecules that target RNA used clinically - the linezolid antibiotics. However, a growing number of small-molecule RNA ligands are being identified, leading to burgeoning interest in the field. Here, we discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures - namely, in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. If focus is placed on such druggable binding sites in RNA, extensive knowledge of the typical physicochemical properties of drug-like small molecules could then enable small-molecule drug discovery for RNA targets to become (only) roughly as difficult as for protein targets.

Expanding the medicinal chemistry synthetic toolbox

Abstract: The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.

New approaches and challenges to targeting the endocannabinoid system.

Abstract: The endocannabinoid signalling system was discovered because receptors in this system are the targets of compounds present in psychotropic preparations of Cannabis sativa. The search for new therapeutics that target endocannabinoid signalling is both challenging and potentially rewarding, as endocannabinoids are implicated in numerous physiological and pathological processes. Hundreds of mediators chemically related to the endocannabinoids, often with similar metabolic pathways but different targets, have complicated the development of inhibitors of endocannabinoid metabolic enzymes but have also stimulated the rational design of multi-target drugs. Meanwhile, drugs based on botanical cannabinoids have come to the clinical forefront, synthetic agonists designed to bind cannabinoid receptor 1 with very high affinity have become a societal threat and the gut microbiome has been found to signal in part through the endocannabinoid network. The current development of drugs that alter endocannabinoid signalling and how this complex system could be pharmacologically manipulated in the future are described in this Opinion article.

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Abstract: Neurodegenerative disorders of ageing such as Alzheimer disease, Parkinson disease and Huntington disease are characterized by the presence of neurotoxic misfolded and aggregated proteins. One reason underlying the accumulation of these proteins is insufficient clearance by intracellular and extracellular pathways such as the autophagic–lysosomal network and the glymph system. This article reviews the potential for therapeutically enhancing the clearance of neurotoxic proteins to curtail the onset and slow the progression of neurodegenerative disorders of ageing. Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic–lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.

Trial watch: The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors.

Abstract: Since the first clinical trial to test a PD1-targeted monoclonal antibody (mAb) — nivolumab — was initiated in 2006, six mAbs targeting either PD1 or its ligand PDL1 have been approved by the FDA to treat 14 cancer types and one histology-agnostic indication. Anti-PD1/PDL1 agents serve as the backbone of the expanding approaches in the immuno-oncology field. Meanwhile, the growth in the number of active clinical trials testing anti-PD1/PDL1 agents has been dramatic, increasing from 1 in 2006 to 2,250 as of September 2018. The Cancer Research Institute, a nonprofit organization dedicated to research in cancer immunotherapy for more than 65 years, analysed the current landscape of clinical trials evaluating these agents and compared the current landscape with the previous one surveyed by us in September 2017 (Ann. Oncol. 29, 84–89; 2017). Since the above mentioned survey, 748 new trials had been started as of September 2018 (FIG. 1a), amounting to a total of 2,250 active trials. Of the 2,250 active trials, 1,716 T R I A L WAT C H

Cryo-EM in drug discovery: achievements, limitations and prospects

Abstract: Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances - including the development of direct electron detectors and more effective computational image analysis techniques - are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies. These advances have raised hopes that single-particle cryo-EM might soon become an important tool for drug discovery, particularly if they could enable structural determination for 'intractable' targets that are still not accessible to X-ray crystallographic analysis. This article describes the recent advances in the field and critically assesses their relevance for drug discovery as well as discussing at what stages of the drug discovery pipeline cryo-EM can be useful today and what to expect in the near future.

Unexplored therapeutic opportunities in the human genome.

Abstract: A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.

Drug development in the era of precision medicine

Abstract: For the past three decades, the use of genomics to inform drug discovery and development pipelines has generated both excitement and scepticism. Although earlier efforts successfully identified some new drug targets, the overall clinical efficacy of developed drugs has remained unimpressive, owing in large part to the heterogeneous causes of disease. Recent technological and analytical advances in genomics, however, have now made it possible to rapidly identify and interpret the genetic variation underlying a single patient's disease, thereby providing a window into patient-specific mechanisms that cause or contribute to disease, which could ultimately enable the 'precise' targeting of these mechanisms. Here, we first examine and highlight the successes and limitations of the earlier phases of genomics in drug discovery and development. We then review the current major efforts in precision medicine and discuss the potential broader utility of mechanistically guided treatments going forward.

Impact of a five-dimensional framework on R&D productivity at AstraZeneca

Abstract: In 2011, AstraZeneca embarked on a major revision of its research and development (R&D) strategy with the aim of improving R&D productivity, which was below industry averages in 2005-2010. A cornerstone of the revised strategy was to focus decision-making on five technical determinants (the right target, right tissue, right safety, right patient and right commercial potential). In this article, we describe the progress made using this '5R framework' in the hope that our experience could be useful to other companies tackling R&D productivity issues. We focus on the evolution of our approach to target validation, hit and lead optimization, pharmacokinetic/pharmacodynamic modelling and drug safety testing, which have helped improve the quality of candidate drug nomination, as well as the development of the right culture, where 'truth seeking' is encouraged by more rigorous and quantitative decision-making. We also discuss where the approach has failed and the lessons learned. Overall, the continued evolution and application of the 5R framework are beginning to have an impact, with success rates from candidate drug nomination to phase III completion improving from 4% in 2005-2010 to 19% in 2012-2016.

The promise and challenges of immune agonist antibody development in cancer.

Abstract: Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development. This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.

Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome

Abstract: Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

Gene therapy for neurological disorders: progress and prospects

Abstract: Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Erratum: Targeting the NLRP3 inflammasome in inflammatory diseases

Abstract: Nature Reviews Drug Discovery 17, 588–606 (2018) A sentence mentioning the authors of reference 122 has been amended to include both corresponding authors.

Regulatory T cells in the treatment of disease

Abstract: Regulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer.

Emptying the stores: lysosomal diseases and therapeutic strategies

Abstract: Lysosomal storage disorders (LSDs) - designated as 'orphan' diseases - are inborn errors of metabolism caused by defects in genes that encode proteins involved in various aspects of lysosomal homeostasis. For many years, LSDs were viewed as unattractive targets for the development of therapies owing to their low prevalence. However, the development and success of the first commercial biologic therapy for an LSD - enzyme replacement therapy for type 1 Gaucher disease - coupled with regulatory incentives rapidly catalysed commercial interest in therapeutically targeting LSDs. Despite ongoing challenges, various therapeutic strategies for LSDs now exist, with many agents approved, undergoing clinical trials or in preclinical development.

Mechanistic enzymology in drug discovery: a fresh perspective

Abstract: Given the therapeutic and commercial success of small-molecule enzyme inhibitors, as exemplified by kinase inhibitors in oncology, a major focus of current drug-discovery and development efforts is on enzyme targets. Understanding the course of an enzyme-catalysed reaction can help to conceptualize different types of inhibitor and to inform the design of screens to identify desired mechanisms. Exploiting this information allows the thorough evaluation of diverse compounds, providing the knowledge required to efficiently optimize leads towards differentiated candidate drugs. This review highlights the rationale for conducting high-quality mechanistic enzymology studies and considers the added value in combining such studies with orthogonal biophysical methods.

Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs.

Abstract: Existing therapeutic strategies for managing Parkinson disease (PD), which focus on addressing the loss of dopamine and dopaminergic function linked with degeneration of dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent decades, research into PD pathophysiology and pharmacology has focused on understanding and tackling the neurodegenerative processes and symptomology of PD. In this Review, we discuss the challenges associated with the development of novel therapies for PD, highlighting emerging agents that aim to target cell death, as well as new targets offering a symptomatic approach to managing features and progression of the disease.

Chemical probes and drug leads from advances in synthetic planning and methodology.

Abstract: Screening of small-molecule libraries is a productive method for identifying both chemical probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chemical space efficiently by populating small-molecule libraries with compounds containing structural features that are typically under-represented in commercially available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chemistry, and we illustrate the impact of the resultant chemical probes and drug leads in a wide range of diseases.