Review Articles in 2017

Efforts to combat bacterial infections by targeting virulence factors are gaining traction, fuelled by the potential to circumvent the development of antibacterial resistance and recent landmark approvals of antivirulence drugs. Here, Otto and colleagues examine the antivirulence drugs in development, highlighting the most promising targets and strategies, as well as caveats to using this approach.

Genome editing has emerged as an attractive approach to therapeutically manipulate gene expression. Here, Anderson and colleagues provide an overview of genome-editing platforms, focusing on the methods and challenges of intracellular biomacromolecule delivery. Preclinical and clinical trials involving genome-editing technologies are also discussed.

Antibody–drug conjugate (ADCs), which aim to target highly cytotoxic drugs specifically to cancer cells, are one of the fastest growing classes of anticancer therapeutics, with more than 50 such agents currently in clinical trials. This Review discusses lessons learned and emerging strategies in the development of ADCs, including aspects such as target selection, the development of warheads, the optimization of linkers and new conjugation chemistries, and provides an overview of agents that are currently in clinical trials.

Changes in glutamate signalling have been implicated in major depression, and ketamine, which was recently found to act as a rapid-acting antidepressant, affects glutamate signalling in several ways. Murrough and colleagues give an overview of the development of glutamate-signalling modulators for depression and examine studies on the mechanisms of these agents.

Human cancers commonly have mutations in epigenetic regulatory genes, and several small molecules that target epigenetic regulators are in clinical trials. Here, Pfister and Ashworth discuss the biological complexity of epigenetic regulation in cancer and provide an overview of inhibitors that target gain-of-function mutations, as well as synthetic lethal approaches to target loss-of-function mutations in epigenetic regulators.

Inhibition of proteins other than the intended target by small molecules can lead to the incorrect assignment of biological functions to particular proteins and wasted drug development efforts. Potential inhibition of off-target kinases by kinase inhibitors is often investigated, but kinase inhibitors can also inhibit non-kinases. Munoz examines the growing number of examples of this issue and suggests a systematic strategy to verify which protein is responsible for the effects of a given small molecule.

MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic.

Lipid second messengers such as phosphatidic acid (PtdOH) have a role in a wide range of pathological processes, and phospholipase D (PLD) enzymes are one of the major sources of signal-activated PtdOH generation. In this Review, Brown, Thomas and Lindsley discuss the development of PLD inhibitors, with a focus on isoform-specific inhibitors, and their potential applications in the treatment of cancer, neurodegeneration and infection.

The B cell lymphoma 2 (BCL-2) family of proteins has a key role in regulating apoptosis and is often dysregulated in cancer. This has led to the development of several inhibitors of pro-survival BCL-2 family proteins such as BCL-2, BCL-X_Land MCL1, including the BCL-2 inhibitor venetoclax, which has recently gained regulatory approval. Here, Ashkenazi and colleagues discuss the latest progress in developing small-molecule inhibitors of pro-survival BCL-2 family proteins.

Dysregulation of iron homeostasis occurs in haematological disorders and in other diseases such as cancer and neurodegeneration. Crielaard and colleagues discuss the progress made in interfering with iron metabolism as a therapeutic strategy, as well as in using iron metabolism to direct drugs to target tissues.

Chemogenomic screening is increasingly being applied to expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Here, Jones and Bunnage discuss the principles of the creation and use of chemogenomic libraries, highlighting key examples and their applications, including target identification, drug repositioning and predictive toxicology.

Immune checkpoint blockade is a powerful anticancer approach; however, it only works for some patients. Here, Lesterhuis and colleagues argue that response to immune checkpoint blockade is a critical state transition of a complex system. They discuss recent advances in mathematics and network biology that might facilitate the identification of dynamic biomarkers, which in turn might help distinguish responders from non-responders and determine new targets for combination therapy.