Volume 18 Issue 12, December 2019

Five anti-cancer KRAS inhibitors, with three different modes of action, are in the clinic. More are on the way.

RNA epigenetic drug development enters a new era, as companies start revealing targets and evidence of preclinical efficacy.

The pathophysiological complexity of progressive multiple sclerosis (MS) challenges the development of effective treatments, despite the substantial unmet clinical need. In this Review, Faissner, Yong and colleagues highlight the need for therapies that target inflammation, neurodegeneration and remyelination, which will likely be needed in combination. The setbacks encountered so far and future challenges are also discussed.

Defective lysosomal function has been implicated in diseases ranging from rare lysosomal storage disorders to more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. Here, Muller and colleagues provide an overview of the physiological and pathological roles of lysosomes and assess the progress and opportunities for therapeutically targeting lysosomal proteins and processes.

Small molecules that induce targeted protein degradation by the ubiquitin–proteasome system, such as proteolysis-targeting chimeras (PROTACs), are attracting great interest as a new therapeutic modality. This Perspective discusses opportunities and challenges for expanding the applicability of targeted protein degradation, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.