scholarly journals Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases

2021 ◽  
Vol 22 (12) ◽  
pp. 6213
Author(s):  
Seonghyeon Moon ◽  
Srinivasan Muniyappan ◽  
Sung-Bae Lee ◽  
Byung-Hoon Lee

The 26S proteasome is the principal protease for regulated intracellular proteolysis. This multi-subunit complex is also pivotal for clearance of harmful proteins that are produced throughout the lifetime of eukaryotes. Recent structural and kinetic studies have revealed a multitude of conformational states of the proteasome in substrate-free and substrate-engaged forms. These conformational transitions demonstrate that proteasome is a highly dynamic machinery during substrate processing that can be also controlled by a number of proteasome-associated factors. Essentially, three distinct family of deubiquitinases–USP14, RPN11, and UCH37–are associated with the 19S regulatory particle of human proteasome. USP14 and UCH37 are capable of editing ubiquitin conjugates during the process of their dynamic engagement into the proteasome prior to the catalytic commitment. In contrast, RPN11-mediated deubiquitination is directly coupled to substrate degradation by sensing the proteasome’s conformational switch into the commitment steps. Therefore, proteasome-bound deubiquitinases are likely to tailor the degradation events in accordance with substrate processing steps and for dynamic proteolysis outcomes. Recent chemical screening efforts have yielded highly selective small-molecule inhibitors for targeting proteasomal deubiquitinases, such as USP14 and RPN11. USP14 inhibitors, IU1 and its progeny, were found to promote the degradation of a subset of substrates probably by overriding USP14-imposed checkpoint on the proteasome. On the other hand, capzimin, a RPN11 inhibitor, stabilized the proteasome substrates and showed the anti-proliferative effects on cancer cells. It is highly conceivable that these specific inhibitors will aid to dissect the role of each deubiquitinase on the proteasome. Moreover, customized targeting of proteasome-associated deubiquitinases may also provide versatile therapeutic strategies for induced or repressed protein degradation depending on proteolytic demand and cellular context.

2008 ◽  
pp. 51-78
Author(s):  
Huib Ovaa ◽  
Herman S. Overkleeft ◽  
Benedikt M. Kessler ◽  
Hidde L. Ploegh

Amino Acids ◽  
2021 ◽  
Author(s):  
James M. Phang

AbstractIn the 35 years since the introduction of the “proline cycle”, its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.


2018 ◽  
Vol 37 (17) ◽  
Author(s):  
Matous Hrdinka ◽  
Lisa Schlicher ◽  
Bing Dai ◽  
Daniel M Pinkas ◽  
Joshua C Bufton ◽  
...  

Author(s):  
Shuting Gao ◽  
Xitong Li ◽  
Miao Zhang ◽  
Ning Zhang ◽  
Ruiyong Wang ◽  
...  

Studies have shown that the FTO gene is closely related to obesity and weight gain in humans. FTO is an N6-methyladenosine demethylase and is linked to an increased risk of obesity and a variety of diseases, such as acute myeloid leukemia, type 2 diabetes, breast cancer, glioblastoma and cervical squamous cell carcinoma. In light of the significant role of FTO, the development of small-molecule inhibitors targeting the FTO protein provides not only a powerful tool for grasping the active site of FTO but also a theoretical basis for the design and synthesis of drugs targeting the FTO protein. This review focuses on the structural characteristics of FTO inhibitors and discusses the occurrence of obesity and cancer caused by FTO gene overexpression.


Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4192 ◽  
Author(s):  
Kenneth I. Onyedibe ◽  
Modi Wang ◽  
Herman O. Sintim

Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) was identified several decades ago as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities, critical for purinergic signaling. Recently, ENPP1 has emerged as a critical phosphodiesterase that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP–AMP (cGAMP). cGAMP or analogs thereof have emerged as potent immunostimulatory agents, which have potential applications in immunotherapy. This emerging role of ENPP1 has placed this “old” enzyme at the frontier of immunotherapy. This review highlights the roles played by ENPP1, the mechanism of cGAMP hydrolysis by ENPP1, and small molecule inhibitors of ENPP1 with potential applications in diverse disease states, including cancer.


Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 375-376
Author(s):  
Robert Zeiser

Edited by Associate Editor Robert Zeiser, this Review Series presents the current understanding of the pathophysiology of and therapeutic approaches to acute graft-versus-host disease (aGVHD). The articles discuss the role of the microbiome in contributing to aGVHD and review how novel cellular therapies, biologicals, and small-molecule inhibitors may advance its treatment.


2008 ◽  
pp. 51-78
Author(s):  
Huib Ovaa ◽  
Herman S. Overkleeft ◽  
Benedikt M. Kessler ◽  
Hidde L. Ploegh

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