Target validation

Target validation is the process by which the predicted molecular target – for example protein or nucleic acid – of a small molecule is verified. Target validation can include: determining the structure-activity-relationship of analogs of the small molecule; generating a drug-resistant mutant of the presumed target; knockdown or overexpression of the presumed target; and monitoring the known signalling systems downstream of the presumed target.

Latest Research and Reviews

  • Research |

    MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, inactivates NLRP3, including hyperactive disease-linked mutations, by closing the ‘open’ conformation, thereby preventing conformational changes required for NLRP3 activation.

    • Ana Tapia-Abellán
    • , Diego Angosto-Bazarra
    • , Helios Martínez-Banaclocha
    • , Carlos de Torre-Minguela
    • , Jose P. Cerón-Carrasco
    • , Horacio Pérez-Sánchez
    • , Juan I. Arostegui
    •  & Pablo Pelegrin
  • Reviews |

    Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Research advances have unveiled unexpected disease-associated alterations in human ARSs that have highlighted their potential as therapeutic targets. This Review addresses the emerging biology and therapeutic applications of human ARSs.

    • Nam Hoon Kwon
    • , Paul L. Fox
    •  & Sunghoon Kim
  • Research | | open

    Diana Carvalho, Kathryn R. Taylor et al. show that ALK2 inhibitors induce apoptosis of ACVR1 mutant diffuse intrinsic pontine glioma cells in vitro. These compounds also increase the survival of mice carrying ACVR1 mutant brainstem xenografts, suggesting ALK2 as a potential pharmacological target against this lethal cancer.

    • Diana Carvalho
    • , Kathryn R. Taylor
    • , Nagore Gene Olaciregui
    • , Valeria Molinari
    • , Matthew Clarke
    • , Alan Mackay
    • , Ruth Ruddle
    • , Alan Henley
    • , Melanie Valenti
    • , Angela Hayes
    • , Alexis De Haven Brandon
    • , Suzanne A. Eccles
    • , Florence Raynaud
    • , Aicha Boudhar
    • , Michelle Monje
    • , Sergey Popov
    • , Andrew S. Moore
    • , Jaume Mora
    • , Ofelia Cruz
    • , Mara Vinci
    • , Paul E. Brennan
    • , Alex N. Bullock
    • , Angel Montero Carcaboso
    •  & Chris Jones
  • Research | | open

    A key challenge is to find/re-purpose approved drugs that could be used in humans to induce autophagy-associated clearance of neurodegenerative proteins. Here, authors demonstrate that felodipine, an anti-hypertensive drug, can induce autophagy and clear a variety of aggregated neurodegenerative disease-associated proteins in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug.

    • Farah H. Siddiqi
    • , Fiona M. Menzies
    • , Ana Lopez
    • , Eleanna Stamatakou
    • , Cansu Karabiyik
    • , Rodrigo Ureshino
    • , Thomas Ricketts
    • , Maria Jimenez-Sanchez
    • , Miguel Angel Esteban
    • , Liangxue Lai
    • , Micky D. Tortorella
    • , Zhiwei Luo
    • , Hao Liu
    • , Emmanouil Metzakopian
    • , Hugo J. R. Fernandes
    • , Andrew Bassett
    • , Eric Karran
    • , Bruce L. Miller
    • , Angeleen Fleming
    •  & David C. Rubinsztein

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