Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

Chen, Hao; Wu, Guozhen; Gao, Shuang; Guo, Ruihua; Zhao, Zichen; Yuan, Haichao; Liu, Shanxiang; Wu, Jian; Lü, Xiaolong; Xing, Yuan; Yu, Zongmin; Zu, Xianpeng; Xie, Ning; Yang, Niao; Hu, Zhenlin; Sun, Qian; Zhang, Guoqing

doi:10.1021/acs.jmedchem.6b01829

Cited by 34 publications

(28 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The surface of the sensor chip was regenerated via the injection of 10 μL of the regeneration buffer (5 mM NaOH). The association rate constant k a and dissociation rate constant k d were calculated and analyzed using the monovalent analyte model, and the equilibrium dissociation constant (KD) was calculated (KD = k d /k a ) [29].…”

Section: Binding Affinity Analysis Using Biacore Surface Plasmon Resomentioning

confidence: 99%

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Lei

Alvarado³

et al. 2020

J Hematol Oncol

View full text Add to dashboard Cite

Background Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. Methods High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. Results We identified a small molecular inhibitor, “MNPC,” that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Conclusions Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.

show abstract

Section: Binding Affinity Analysis Using Biacore Surface Plasmon Resomentioning

confidence: 99%

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Lei

Alvarado³

et al. 2020

J Hematol Oncol

View full text Add to dashboard Cite

show abstract

“…To date, approximately twenty inhibitors of ubiquitin-conjugating E2 enzymes have been discovered (Ardecky et al, 2010; Ceccarelli et al, 2011; Chen et al, 2017; Cheng et al, 2014; Cornwell et al, 2019; Garg et al, 2020; Helms et al, 2011; Kothayer et al, 2016; Liu et al, 2014; Pulvino et al, 2012; Sanders et al, 2013; Strickson et al, 2013; Wang et al, 2018, 2011). Many of the reported inhibitors target the active site Cys, others act by disrupting protein-protein interactions, and some have an allosteric effect on ubiquitin transfer.…”

Section: Discussionmentioning

confidence: 99%

Identification of ubiquitin variants that inhibit the E2 ubiquitin conjugating enzyme, Ube2k

Middleton

Teyra

Zhu

et al. 2021

Preprint

View full text Add to dashboard Cite

Transfer of ubiquitin to substrate proteins regulates most processes in eukaryotic cells. E2 enzymes are a central component of the ubiquitin machinery, and generally determine the type of ubiquitin signal generated and thus the ultimate fate of substrate proteins. The E2, Ube2k, specifically builds degradative ubiquitin chains on diverse substrates. Here we have identified protein-based reagents, called ubiquitin variants (UbVs), that bind tightly and specifically to Ube2k. Crystal structures reveal that the UbVs bind to the E2 enzyme at a hydrophobic cleft that is distinct from the active site and previously identified ubiquitin binding sites. We demonstrate that the UbVs are potent inhibitors of Ube2k and block both ubiquitin charging of the E2 enzyme, and E3-catalysed ubiquitin transfer. The binding site of the UbVs suggests they directly clash with the ubiquitin activating enzyme, while potentially disrupting interactions with E3 ligases via allosteric effects. Our data reveal the first protein-based inhibitors of Ube2k and unveil a hydrophobic groove that could be an effective target for inhibiting Ube2k and other E2 enzymes.

show abstract

“…Diverse butyrolactones have been studied to evaluate anti-inflammatory activities (Entry 1-9 in Table 2). Some of these butyrolactones modulate the NF-κB signaling pathway such as a santonine-derived butyrolactone that showed anti-inflammatory activity through the inhibition of the ubiquitin-conjugating enzyme, UbcH5c (Entry 1 in Table 2) [23,24]. This anti-inflammatory activity was maintained in vivo using Freund's adjuvant arthritis rat model.…”

Section: Biologically Active γ-Butyrolactones 221 Anti-inflammationmentioning

confidence: 99%

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

Hur

Jang

Sim

2021

IJMS

View full text Add to dashboard Cite

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.

show abstract

Discovery of Potent Small-Molecule Inhibitors of Ubiquitin-Conjugating Enzyme UbcH5c from α-Santonin Derivatives

Cited by 34 publications

References 49 publications

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Identification of ubiquitin variants that inhibit the E2 ubiquitin conjugating enzyme, Ube2k

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones

Contact Info

Product

Resources

About