Inhibition of the human ubiquitin-specific protease 7 (USP7), the key deubiquitylating enzyme in regulating p53 protein levels, has been considered an attractive anticancer strategy. In order to enhance the cellular activity of FT671, scaffold hopping strategy was employed. This endeavor resulted in the discovery of YCH2823, a novel and potent USP7 inhibitor.YCH2823 demonstrated remarkable efficacy in inhibiting the growth of a specific subset of TP53 wild-type, -mutant, and MYCN-amplified cell lines, surpassing the potency of FT671 by approximately 5-fold. The mechanism of action of YCH2823 involves direct interaction with the catalytic domain of USP7, thereby impeding the cleavage of ubiquitinated substrates. An increase in the expression of p53 and p21, accompanied by G1 phase arrest and apoptosis, was observed upon treatment with YCH2823. Subsequently, the knockdown of p53 or p21 in CHP-212 cells exhibited a substantial reduction in sensitivity to YCH2823, as evidenced by a considerable increase in IC₅₀ values up to 690-fold. Furthermore, YCH2823 treatment specifically enhanced the transcriptional and protein levels of BCL6 in sensitive cells. Moreover, a synergistic effect between USP7 inhibitors and mTOR inhibitors was observed, suggesting the possibility of novel therapeutic strategies for cancer treatment. In conclusion, YCH2823 exhibits potential as an anticancer agent for the treatment of both TP53 wild-type and -mutant tumors.

2018-12-01·Cell Research1区 · 生物学

Small molecule inhibitors reveal allosteric regulation of USP14 via steric blockade

1区 · 生物学

Article

作者: Li, Bin ; Li, Jiawang ; Song, Ningjing ; Ren, Yujing ; Mei, Ziqing ; Ding, Shan ; Wu, Cai ; Hong, Danning ; Wang, Yiwei ; He, Wei ; Wang, Jiawei ; Wang, Feng ; Jiang, Yuxuan

The ubiquitin system is important for drug discovery, and the discovery of selective small-molecule inhibitors of deubiquitinating enzymes (DUBs) remains an active yet extremely challenging task. With a few exceptions, previously developed inhibitors have been found to bind the evolutionarily conserved catalytic centers of DUBs, resulting in poor selectivity. The small molecule IU1 was the first-ever specific inhibitor identified and exhibited surprisingly excellent selectivity for USP14 over other DUBs. However, the molecular mechanism for this selectivity was elusive. Herein, we report the high-resolution co-crystal structures of the catalytic domain of USP14 bound to IU1 and three IU1 derivatives. All the structures of these complexes indicate that IU1 and its analogs bind to a previously unknown steric binding site in USP14, thus blocking the access of the C-terminus of ubiquitin to the active site of USP14 and abrogating USP14 activity. Importantly, this steric site in USP14 is very unique, as suggested by structural alignments of USP14 with several known DUB X-ray structures. These results, in conjunction with biochemical characterization, indicate a coherent steric blockade mechanism for USP14 inhibition by compounds of the IU series. In light of the recent report of steric blockade of USP7 by FT671, this work suggests a potential generally applicable allosteric mechanism for the regulation of DUBs via steric blockade, as showcased by our discovery of IU1-248 which is 10-fold more potent than IU1.

2017-10-01·Nature1区 · 综合性期刊

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

1区 · 综合性期刊

Article

作者: McGouran, Joanna F ; Turnbull, Andrew P ; Alli, Cristina ; Hammonds, Tim R ; Clague, Michael J ; Evans, Nicola J ; Wang, Minghua ; Charlton, Thomas M ; Zarayskiy, Vladislav V ; Lahdenranta, Johanna ; Raynham, Tony M ; Wilker, Erik ; Toms, Angela V ; Marshall, C Gary ; Simcox, Mary ; Talbot, Adam C ; Urbé, Sylvie ; McLoughlin, Sheila B ; Kessler, Benedikt M ; Stead, Lucy ; Bair, Kenneth W ; Century, Hannah ; Dinsmore, Christopher J ; Buker, Shane M ; Saab, Fabienne ; Caravella, Justin A ; Krajewski, Wojciech W ; Heride, Claire ; Ioannidis, Stephanos ; Lancia, David R ; Townsend, Elizabeth C ; Pittman, Marc S ; Buckmelter, Alexandre J ; Escobedo, Jaime A ; McKinnon, Crystal L ; Martin, Agnes C L ; Komander, David ; Pinto-Fernandez, Adan ; Kim, Sunkyu ; Tonkin, Louise M ; Follows, Bruce C ; Stewart, Lorna M D ; Gersch, Malte

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

100 项与 FT-671 相关的药物交易

登录后查看更多信息