GNE-6640 is a selective inhibitor of ubiquitin specific protease-7 (USP7) (IC50 = 0.75 μM) that can induce tumor cell death and enhance the effect of chemotherapy drugs.
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-6640 is a selective and non-covalent inhibitor of USP7, with IC50 values of 0.75 μM, 0.43 μM, 20.3 μM and 0.23 μM for full length USP7, USP7 catalytic domain, full length USP43 and Ub-MDM2, respectively[2]. GNE-6640 promoted endogenous MDM2 ubiquitination with Lys48 (K48)-linked polyubiquitin chains, which direct proteasomal degradation and it targeted cellular USP7, MDM2, and p53 signalling pathways[2]. GNE-6640 decreased viability of 54 cell lines with IC50 ≤ 10 μM. Acute myeloid leukaemia (AML) cell lines had increased sensitivity to GNE-6640[2]. Combining GNE-6640 with doxorubicin or cisplatin (DNA-damaging agents) could activate the p53 response and enhance USP7 inhibitory efficacy. GNE-6640 could also induce tumor cell death and enhance cytotoxicity with chemotherapeutic agents and targeted compounds, including PIM kinase inhibitors[2].
作用机制
GNE-6640 interacts with acidic residues that mediate hydrogen-bond interactions with the ubiquitin Lys48 side chain.
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