Read the December issue

Including articles on expanding the toolbox for targeted protein degradation, therapeutic strategies for multiple sclerosis, lysosomes as targets, and cracking the 'undruggable' cancer target KRAS.

Latest Reviews

  • Perspective |

    Artificial intelligence (AI) tools are increasingly being applied in drug discovery. This article presents the views of a group of international experts on the ‘grand challenges’ in small-molecule drug discovery with AI, including obtaining appropriate data sets, generating new hypotheses, optimizing in a multi-objective manner, reducing cycle times and changing the research culture.

    • Petra Schneider
    • , W. Patrick Walters
    • , Alleyn T. Plowright
    • , Norman Sieroka
    • , Jennifer Listgarten
    • , Robert A. Goodnow Jr.
    • , Jasmin Fisher
    • , Johanna M. Jansen
    • , José S. Duca
    • , Thomas S. Rush
    • , Matthias Zentgraf
    • , John Edward Hill
    • , Elizabeth Krutoholow
    • , Matthias Kohler
    • , Jeff Blaney
    • , Kimito Funatsu
    • , Chris Luebkemann
    •  & Gisbert Schneider
  • Perspective |

    Current preclinical models poorly predict the potential of a new drug candidate to cause drug-induced liver injury (DILI) in humans. Here, Park and colleagues discuss current understanding of the mechanisms mediating DILI and, through an academic–industry collaboration, propose a roadmap for the development of predictive preclinical models of human DILI.

    • Richard J. Weaver
    • , Eric A. Blomme
    • , Amy E. Chadwick
    • , Ian M. Copple
    • , Helga H. J. Gerets
    • , Christopher E. Goldring
    • , Andre Guillouzo
    • , Philip G. Hewitt
    • , Magnus Ingelman-Sundberg
    • , Klaus Gjervig Jensen
    • , Satu Juhila
    • , Ursula Klingmüller
    • , Gilles Labbe
    • , Michael J. Liguori
    • , Cerys A. Lovatt
    • , Paul Morgan
    • , Dean J. Naisbitt
    • , Raymond H. H. Pieters
    • , Jan Snoeys
    • , Bob van de Water
    • , Dominic P. Williams
    •  & B. Kevin Park
  • Review Article |

    Genomic screenings have enabled the discovery of synthetic lethal partners as potential drug targets in cancer. This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.

    • Alan Huang
    • , Levi A. Garraway
    • , Alan Ashworth
    •  & Barbara Weber
  • Perspective |

    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.

    • Matthieu Schapira
    • , Matthew F. Calabrese
    • , Alex N. Bullock
    •  & Craig M. Crews
  • Review Article |

    Cell plasticity has emerged as a mode of targeted therapy evasion in various cancers. This Review discusses the different mechanisms that drive tumour cell plasticity and the potential therapeutic strategies to target them in order to achieve more durable clinical responses.

    • Soufiane Boumahdi
    •  & Frederic J. de Sauvage
  • Review Article |

    Precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3′ ends by cleavage and polyadenylation, is frequently altered in tumours. This Review describes small molecules and oligonucleotides that modulate the spliceosome and are now in clinical trials for the treatment of cancer.

    • Joana Desterro
    • , Pedro Bak-Gordon
    •  & Maria Carmo-Fonseca

News & Comment

  • An Audience With |

    With Takeda’s US$62 billion acquisition of Shire in 2018, the Japanese firm scored a spot as a top 10 pharmaceutical firm. But well before the deal was even on the radar, President of R&D Andy Plump and CEO Christophe Weber were already working to transform the company. Once a small-molecule specialist, it is now embracing new modalities to be better positioned to follow the biology of disease. Once internally focused, it is now partnering whenever possible both to bring compelling new projects in and to let promising assets out. And Plump, now celebrating 5 years at the firm, is ready to showcase Takeda’s new look. He spoke with Asher Mullard about Takeda’s plans to leapfrog competitors in immuno-oncology, cellular therapy, rare diseases, gene therapy and more.

    • Asher Mullard
  • Poster |

    The complement pathway plays key roles in host defence, but its excessive activation or dysregulation can lead to a variety of disorders. This poster overviews strategies to therapeutically intervene in the pathway and the new generation of complement inhibitors that are now in the clinic.

    • Daniel Ricklin
    • , Dimitrios C. Mastellos
    •  & John D. Lambris

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