The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

2010 ◽  
pp. 1-56
Author(s):  
Roland W. Bürli ◽  
Elizabeth Thomas ◽  
Vahri Beaumont
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecule ◽  
Histone Deacetylases ◽  
Therapeutic Approach ◽  
Small Molecule Inhibitors

scholarly journals KRAS is vulnerable to reversible switch-II pocket engagement in cells

2021 ◽  
Author(s):  
James D Vasta ◽  
D. Matthew Peacock ◽  
Qinheng Zheng ◽  
Joel A Walker ◽  
Ziyang Zhang ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
Binding Site ◽  
Small Molecule ◽  
Therapeutic Approach ◽  
Small Molecule Inhibitors ◽  
Drug Binding ◽  
Gtp Hydrolysis ◽  
Drug Binding Site ◽  
Covalent Ligands ◽  
P Ligands

Current small molecule inhibitors of KRAS (G12C) bind irreversibly in the switch-II pocket, exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the switch-II pocket is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a novel cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the switch-II pockets of many GTP hydrolysis-deficient KRAS hotspot (G12, G13, Q61) mutants are accessible using non-covalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the switch-II pocket as a privileged drug binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.

scholarly journals Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

Amino Acids ◽  
2021 ◽  
Author(s):  
James M. Phang
Keyword(s):  
Extracellular Matrix ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Human Tumors ◽  
Regulatory Link

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.

scholarly journals Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies

2015 ◽  
Vol 12 (9) ◽  
pp. 814-828 ◽  
Author(s):  
Marcus Pickhardt ◽  
Thomas Neumann ◽  
Daniel Schwizer ◽  
Kari Callaway ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Approach ◽  
Small Molecule Inhibitors ◽  
Tau Aggregation

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
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Kinetic Studies ◽  
26S Proteasome ◽  
Chemical Screening ◽  
Cellular Context ◽  
Substrate Processing ◽  
Intracellular Proteolysis ◽  
Processing Steps

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.

scholarly journals Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

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

Structural characteristics of small-molecule inhibitors targeting FTO demethylase

2021 ◽  
Author(s):  
Shuting Gao ◽  
Xitong Li ◽  
Miao Zhang ◽  
Ning Zhang ◽  
Ruiyong Wang ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Structural Characteristics ◽  
Cervical Squamous Cell Carcinoma ◽  
Fto Gene ◽  
Design And Synthesis ◽  
Increased Risk ◽  
Obesity And Cancer

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.

Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases

2019 ◽  
Vol 18 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Sorabh Sharma ◽  
K.C. Sarathlal ◽  
Rajeev Taliyan
Keyword(s):  
Neurodegenerative Diseases ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Beneficial Effects ◽  
In Vivo Animal Models ◽  
Preclinical And Clinical Studies

Background & Objective: Imbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored. Conclusion: In this review, we focus on the putative role of HDACs in neurodegeneration and further discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.

scholarly journals ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors—A STING in the Tale of ENPP1

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4192 ◽  
Author(s):  
Kenneth I. Onyedibe ◽  
Modi Wang ◽  
Herman O. Sintim
Keyword(s):  
Small Molecule ◽  
Cyclic Gmp ◽  
Small Molecule Inhibitors ◽  
Purinergic Signaling ◽  
Type Ii ◽  
Disease States ◽  
Transmembrane Glycoprotein ◽  
Nucleotide Pyrophosphatase ◽  
Potential Applications

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.

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