The Francis Crick Institute
Browse

Enantioselective OTUD7B fragment discovery through chemoproteomics screening and high-throughput optimisation.

Download (4.98 MB)
journal contribution
posted on 2025-01-17, 11:06 authored by Aini Vuorinen, Cassandra R Kennedy, Katherine A McPhie, William McCarthy, Jonathan Pettinger, J Mark Skehel, David House, Jacob T Bush, Katrin Rittinger
Deubiquitinating enzymes (DUBs) are key regulators of cellular homoeostasis, and their dysregulation is associated with several human diseases. The ovarian tumour protease (OTU) family of DUBs are biochemically well-characterised and of therapeutic interest, yet only a few tool compounds exist to study their cellular function and therapeutic potential. Here we present a chemoproteomics fragment screening platform for identifying novel DUB-specific hit matter, that combines activity-based protein profiling with high-throughput chemistry direct-to-biology optimisation to enable rapid elaboration of initial fragment hits against OTU DUBs. Applying these approaches, we identify an enantioselective covalent fragment for OTUD7B, and validate it using chemoproteomics and biochemical DUB activity assays.

Funding

Crick (Grant ID: CC1063, Grant title: STP Proteomics) Crick (Grant ID: CC2075, Grant title: Rittinger CC2075) Biotechnology and Biological Sciences Research Council (Grant ID: BB/T014547/1, Grant title: BBSRC BB/T014547/1)

History

Usage metrics

    The Francis Crick Institute

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC