Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival[2]. GNE-6776 is a selective USP7 inhibitor. It non-covalently targets USP7 12 Å distant from the catalytic cysteine and attenuates ubiquitin binding and thus inhibits USP7 deubiquitinase activity. GNE-6776 targets cellular USP7, MDM2, and p53 signaling pathways but selectively inhibits recombinant USP7 relative to 36 other deubiquitinases. Notably, GNE-6776 remains selective even at 100 μM, a more than sixfold higher concentration than used in cellular assays[2]. Although efficacious exposure is only transiently achieved, GNE-6776 causes modest, although significant, EOL-1 xenograft growth delay[2].
作用机制
GNE-6776 interacts with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain.
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