Review Articles, News & Views, Perspectives, Hypotheses, Analyses and Review in 2016

The colony-stimulating factors (CSFs) have roles in inflammation and immunity, and are potential targets for diseases caused by aberrant immune activation, including rheumatoid arthritis and multiple sclerosis. Hamiltonet al. describe how distinguishing attributes could be used to target individual CSFs for therapeutic use in immune and inflammatory conditions and the progress that has been made towards that goal. They also clarify misconceptions about targeting this class of molecules.

Islet transplantation can be an effective therapy for patients with type 1 diabetes, but its widespread use is limited by the need for lifelong immunosuppression. Here, Desai and Shea discuss the emerging potential of islet cell encapsulation including new strategies, assess key challenges facing the human translation of this technology and highlight encapsulation devices that have entered the clinic.

The use of CRISPR–Cas technology for gene editing has rapidly become widespread. Here, Corn and colleagues discuss the applications of this revolutionary tool in drug discovery and development, describing how it could make substantial contributions to target identification and validation, animal models and cell-based therapies.

Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.

DNA-encoded chemistry enables rapid and inexpensive syntheses and screening of vast chemical libraries, and is generating substantial interest and investment in the pharmaceutical industry. Here, Goodnow and colleagues provide an overview of the steps involved in the generation of DNA-encoded libraries, highlighting key applications and future directions for this technology.

The success of mechanism-based drug discovery depends on the definition of the drug target, but targets are often poorly defined in the literature. Here, Overington and colleagues present a comprehensive map of the molecular targets of approved drugs, and explore aspects including the footprint of target classes across disease areas, the success of privileged target families and drug target orthologues across standard model organisms.

Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function. This article discusses emerging technologies, such as proteolysis-targeting chimaeras (PROTACs), that exploit cellular quality control machinery to selectively degrade target proteins, which could have advantages over traditional approaches, including the potential to target proteins that are not currently therapeutically tractable.

The calpain family of proteases are involved in numerous physiological and pathological processes. Here, Sorimachi and colleagues provide an overview of the calpain superfamily and calpain-related disorders, assess the various emerging approaches for therapeutically targeting calpains and highlight agents currently in clinical trials.

Mesenchymal stem cells (MSCs) actively contribute to the formation of the tumour microenvironment by producing various factors that affect tumour growth and response to therapy. Moreover, MSCs can modulate tumour immunity. This Review discusses the various roles of MSCs in cancer and highlights potential strategies to target pro-tumorigenic activities of MSCs or take advantage of the tumour-homing capacity of MSCs for the delivery of drugs.

Nucleic acid aptamers offer several advantages over traditional antibodies, but their clinical translation has been delayed by several factors, including insufficient potency, lack of safety data and high production costs. Here, Zhou and Rossi provide an overview of aptamer generation, focusing on recent technological advances and clinical development, as well as challenges and lessons learned.

The modification of epigenetic markers has become an attractive approach to cancer treatment. Here, Prinjha and colleagues discuss the use of epigenetic modulators in inflammatory diseases, which could be particularly amenable to this approach, as immune memory is often encoded in epigenetic changes. Although the field is still at an early stage, many compounds have been found to be more specific than previously thought and could soon enter clinical trials for autoimmune and inflammatory conditions.

Infection with HIV-1 is currently incurable as HIV-1 can persist as integrated provirus in the genome of latently infected CD4⁺T cells, where it is invisible to the immune system and not responsive to drugs. Here, Ferrari and colleagues discuss the development of novel engineered bispecific and trispecific antibodies, particularly dual-affinity re-targeting (DART) proteins, designed to eradicate latently infected cells.

Myokines are emerging as potential mediators of some of the beneficial effects of exercise on the body. Here, Whitham and Febbraio discuss the challenges facing the discovery and validation of myokines and highlight selected myokines with the potential to be therapeutically exploited in cancer and metabolic disease.

Although the liver has a key role in maintaining blood glucose homeostasis, few existing type 2 diabetes therapies directly target this organ. Here, Puigserveret al. provide an overview of the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, focusing on emerging strategies to target hepatic glucose metabolism for the treatment of diabetes.

Over the past 25 years, biophysical technologies such as X-ray crystallography and nuclear magnetic resonance spectroscopy have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. This article provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways they can be applied at different stages of the drug discovery process.

KRAS is one of the most frequently activated proteins in cancer, yet the development of RAS inhibitors has proven to be extremely challenging. Here, Shokat and Ostrem discuss the latest insights into RAS structure and dynamics, consider potential mechanisms of action for effective RAS inhibitors, and examine recent reports of direct RAS inhibitors.

The progression of prostate cancer to castration-resistant prostate cancer (CRPC) poses considerable therapeutic challenges. Johann de Bono and colleagues review the identification of possible drug targets in CRPC, the evolving CRPC therapeutic landscape and what the future of the treatment of the disease may hold.

Fragment-based methods have made substantial contributions to drug discovery in the past 20 years, particularly for challenging targets. Erlanson and colleagues discuss progress in the field, key aspects such as the design of fragment libraries and the choice of screening technique, and how current challenges in fragment-based drug discovery might be overcome.

The focus of cardiovascular research has changed over the decades, and non-myocytes, including fibroblasts, are becoming increasingly central to our understanding of cardiac function. Kohl and colleagues discuss cardiac fibroblasts, their origins and their expanding roles in homeostasis and tissue repair, and highlight opportunities for therapeutic intervention.

Adipose tissue may become severely dysfunctional during obesity, resulting in disrupted metabolic homeostasis and ultimately type 2 diabetes. Here, Scherer and colleagues provide an overview of adipose tissue development, function and homeostasis, focusing on emerging potential strategies for targeting this organ in the treatment of obesity-associated diabetes.