Drug development articles within Nature

Featured

  • Analysis
    | Open Access

    Human genetic evidence increases the success rate of drugs from clinical development to approval but we are still far from reaching peak genetic insights to aid the discovery of targets for more effective drugs.

    • Eric Vallabh Minikel
    • , Jeffery L. Painter
    •  & Matthew R. Nelson

  • Article
    | Open Access

    RMC-7977, a compound that exhibits potent inhibition of the active states of mutant and wild-type KRAS, NRAS and HRAS variants has a strong anti-tumour effect on RAS-addicted tumours and is well tolerated in preclinical models.

    • Matthew Holderfield
    • , Bianca J. Lee
    •  & Mallika Singh

  • Review Article |

    This Review provides a perspective on the development of non-cancer therapies based on human genetics studies and suggests measures that can be taken to streamline the pipeline from initial genetic discovery to approved therapy.

    • Katerina Trajanoska
    • , Claude Bhérer
    •  & Vincent Mooser

  • Article
    | Open Access

    Whole-genome sequencing analyses in a cohort of individuals with ataxia-telangiectasia are used to identify genetic variants that might be amenable to treatment with splice-switching antisense oligonucleotides (ASOs), and develop ASOs with therapeutic potential.

    • Jinkuk Kim
    • , Sijae Woo
    •  & Timothy W. Yu

  • Article
    | Open Access

    Suppressor tRNAs adapted to the amino acid that they carry enable readthrough of premature termination codons introduced by nonsense mutations and show potential for the treatment of genetic diseases such as cystic fibrosis.

    • Suki Albers
    • , Elizabeth C. Allen
    •  & Zoya Ignatova

  • Article
    | Open Access

    A single dose of a small-molecule HIV capsid inhibitor provides long-term protection from repeated simian–human immunodeficiency virus challenges in macaques and might serve as a novel strategy for HIV prevention in humans.

    • Samuel J. Vidal
    • , Elena Bekerman
    •  & Dan H. Barouch

  • Article |

    Cryo-electron microscopy structures of PCFT in a substrate-free state and bound to the antifolate drug pemetrexed provide insights into how this protein recognizes folates and mediates their transport into cells.

    • Joanne L. Parker
    • , Justin C. Deme
    •  & Simon Newstead

  • Article |

    Crystal structures of the MEK kinase bound to the scaffold protein KSR and various MEK inhibitors, including the anti-cancer drug trametinib, reveal the molecular and functional mechanisms behind MEK inhibition.

    • Zaigham M. Khan
    • , Alexander M. Real
    •  & Arvin C. Dar

  • Article |

    In a dose-escalation study of the COVID-19 RNA vaccine BNT162b1 in 45 healthy adults, RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second vaccine dose.

    • Mark J. Mulligan
    • , Kirsten E. Lyke
    •  & Kathrin U. Jansen

  • Review Article |

    A review of drug resistance in cancer analyses each biological determinant of resistance separately and discusses existing and new therapeutic strategies to combat the problem as a whole.

    • Neil Vasan
    • , José Baselga
    •  & David M. Hyman

  • Article |

    Treatment of KRASG12C-mutant cancer cells with the KRAS(G12C) inhibitor AMG 510 leads to durable response in mice, and anti-tumour activity in patients suggests that AMG 510 could be effective in patients for whom treatments are currently lacking.

    • Jude Canon
    • , Karen Rex
    •  & J. Russell Lipford

  • Letter |

    A proof-of-concept clinical trial of patients with histiocytoses with MAPK-pathway mutations showed durable responses to treatment with the MEK1 and MEK2 inhibitor cobimetinib, which indicates that histiocytic neoplasms are dependent on MAPK signalling.

    • Eli L. Diamond
    • , Benjamin H. Durham
    •  & David M. Hyman

  • Letter |

    In a phase I trial, highly individualized peptide vaccines against unmutated tumour antigens and neoepitopes elicited sustained responses in CD8+ and CD4+ T cells, respectively, in patients with newly diagnosed glioblastoma.

    • Norbert Hilf
    • , Sabrina Kuttruff-Coqui
    •  & Wolfgang Wick

  • Article |

    The structure of a complex containing calcitonin gene-related peptide, the human calcitonin gene-related peptide receptor and the Gs heterotrimer, determined using Volta phase-plate cryo-electron microscopy, provides structural insight into the regulation of G-protein-coupled receptors by receptor activity modifying protein 1.

    • Yi-Lynn Liang
    • , Maryam Khoshouei
    •  & Patrick M. Sexton

  • Article |

    In a basket trial design, the efficacy of the pan-HER kinase inhibitor neratinib is tested in patients with 21 different tumour types, and responses are determined by mutation and tissue type, and are restricted to HER2-mutant cancers.

    • David M. Hyman
    • , Sarina A. Piha-Paul
    •  & David B. Solit

  • Article |

    A high-resolution structure of the human ribosome determined by cryo-electron microscopy visualizes numerous RNA modifications that are concentrated at functional sites with an extended shell, and suggests the possibility of designing more specific ribosome-targeting drugs.

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    •  & Bruno P. Klaholz

  • Letter |

    Mouse models of breast carcinoma and other solid tumours show that selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors not only induce tumour cell cycle arrest but also promote anti-tumour immunity.

    • Shom Goel
    • , Molly J. DeCristo
    •  & Jean J. Zhao

  • Letter |

    The selective allosteric ABL1 inhibitor ABL001 (asciminib) represents a new inhibitory mechanism for BCR–ABL1-driven malignancies, and its efficacy and evolving mechanisms of resistance do not overlap with those of other BCR–ABL1 kinase inhibitors.

    • Andrew A. Wylie
    • , Joseph Schoepfer
    •  & William R. Sellers

  • Article |

    Aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ, reduces soluble and insoluble Aβ in the brain, an action accompanied by a dose-dependent slowing of clinical decline in treated patients.

    • Jeff Sevigny
    • , Ping Chiao
    •  & Alfred Sandrock

  • Letter |

    SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.

    • Ying-Nan P. Chen
    • , Matthew J. LaMarche
    •  & Pascal D. Fortin

  • Letter |

    The discovery is reported of a small molecule drug, GS-5734, which has antiviral activity against Ebola virus and other filoviruses, and is capable of providing post-exposure therapeutic protection against lethal disease in 100% of drug-treated nonhuman primates infected with Ebola virus; the drug targets viral RNA polymerase and can distribute to sanctuary sites (such as testes, eyes and brain), suggesting that it may be able to clear persistent virus infection.

    • Travis K. Warren
    • , Robert Jordan
    •  & Sina Bavari

  • Article |

    This study describes the long-awaited crystal structures for hypoxia-inducible factor (HIF) heterodimers, including complexes bound to small molecules and DNA; the HIF–ARNT architecture is distinct from the bHLH-PAS-containing CLOCK–BMAL1 heterodimer, and HIF mutations linked to cancer can be mapped to important structural regions, with the structures providing future reference for small-molecule drug discovery efforts.

    • Dalei Wu
    • , Nalini Potluri
    •  & Fraydoon Rastinejad

  • Letter |

    Using a structure-based approach, small molecule inhibitors that selectively target the GTPase Ral are identified and characterized; these first-generation inhibitors will be valuable tools for elucidating the Ral signalling pathway and constitute a step towards developing Ral-specific agents for cancer therapy.

    • Chao Yan
    • , Degang Liu
    •  & Dan Theodorescu

  • Outlook |

    The development of effective antiepilepsy drugs is moving on from trial-and-error approaches to sophisticated molecular solutions.

    • Megan Cully

  • Outlook |

    • Herb Brody

  • Outlook |

    Tailoring cancer treatment to individual and evolving tumours is the way of the future, but scientists are still hashing out the details.

    • Lauren Gravitz

  • Outlook |

    In the face of more drug-resistant bugs and fewer new drugs, partnerships promise a resurgence of antibiotics.

    • Mike May

  • Outlook |

    Researchers have made good progress with animal tests for cognition. The next step is to devise a rodent model for drug development.

    • Alla Katsnelson

  • Outlook |

    Schizophrenia debilitates not just by psychosis but by depriving people of the ability to feel pleasure.

    • Elie Dolgin

  • Article |

    A chemoproteomic screen is used here to identify MTH1 as the target of SCH51344, an experimental RAS-dependent cancer drug; a further search for inhibitors revealed (S)-crizotinib as a potent MTH1 antagonist, which suppresses tumour growth in animal models of colon cancer, and could be part of a new class of anticancer drugs.

    • Kilian V. M. Huber
    • , Eidarus Salah
    •  & Giulio Superti-Furga

  • Outlook |

    Tumours can put a brake on the immune system, but new therapies work by removing these brakes. Now, researchers have to figure out how to use them most effectively.

    • Karen Weintraub

  • Outlook |

    Drugs to protect vulnerable neurons and encourage neural circuits to reform could one day improve the outlook for patients with acute spinal cord trauma.

    • Megan Cully

  • Outlook |

    Knowing the structures of G-protein-coupled receptors, says Lindau keynote speaker Brian Kobilka, should help with drug development. But how is this progressing?

    • Monica Hoyos Flight

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