Target Identification of HDAC8 Isoform for the Treatment of Cancer

2019 ◽  
pp. 140-172
Author(s):  
A. Umamaheswari ◽  
A. Puratchikody ◽  
Sakthivel Balasubramaniyan
Keyword(s):  
Histone Deacetylases ◽  
Target Identification ◽  
Therapeutic Index ◽  
Drug Binding ◽  
The Novel ◽  
Post Translational Modifications ◽  
Histone Deacetylases Inhibitors ◽  
Signaling Receptors ◽  
High Degree ◽  
Selective Influence

Target identification has been considered as a chief parameter in drug discovery as it fully characterizes on-target and off-target effects of drug binding. Cell signaling receptors, structural proteins, and post-translational modifications of histones by histone deacetylases are the most widespread targets that are progressively being explored. The FDA approved histone deacetylases inhibitors and the majority of HDACi in and out of clinical trials based on the activities of 11 isoforms of the enzyme in non-selective influence approach. Unfortunately, reported HDACi does not possess a high degree of structural specificity and ultimately lessens the therapeutic index with many dose limiting toxicities. This chapter illustrates how different approaches are incorporated into the novel inhibitors discovery that are truly isoform-selective and which are specifically involved in targeting only a particular isozyme. Further, it highlights the aspects relating to provide a wider therapeutic index with an improved toxicity profile of lead like epigenetic modulators.

scholarly journals Novel late-stage radiosynthesis of 5-[18F]-trifluoromethyl-1,2,4-oxadiazole (TFMO) containing molecules for PET imaging

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nashaat Turkman ◽  
Daxing Liu ◽  
Isabella Pirola
Keyword(s):  
Late Stage ◽  
Histone Deacetylases ◽  
Radiochemical Purity ◽  
Radiochemical Yield ◽  
Single Step ◽  
The Novel ◽  
Molar Activity ◽  
The Central Nervous System ◽  
Class Iia Hdacs ◽  
18F Fluoride

AbstractSmall molecules that contain the (TFMO) moiety were reported to specifically inhibit the class-IIa histone deacetylases (HDACs), an important target in cancer and the disorders of the central nervous system (CNS). However, radiolabeling methods to incorporate the [18F]fluoride into the TFMO moiety are lacking. Herein, we report a novel late-stage incorporation of [18F]fluoride into the TFMO moiety in a single radiochemical step. In this approach the bromodifluoromethyl-1,2,4-oxadiazole was converted into [18F]TFMO via no-carrier-added bromine-[18F]fluoride exchange in a single step, thus producing the PET tracers with acceptable radiochemical yield (3–5%), high radiochemical purity (> 98%) and moderate molar activity of 0.33–0.49 GBq/umol (8.9–13.4 mCi/umol). We validated the utility of the novel radiochemical design by the radiosynthesis of [18F]TMP195, which is a known TFMO containing potent inhibitor of class-IIa HDACs.

scholarly journals A history of uremic toxicity and of the European Uremic Toxin Work Group (EUTox)

2021 ◽  
Author(s):  
Raymond Vanholder ◽  
Angel Argiles ◽  
Joachim Jankowski ◽  
Keyword(s):  
Work Group ◽  
Target Identification ◽  
Kidney Injury ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Post Translational Modifications ◽  
History Of ◽  
Advanced Stages ◽  
Uremic Syndrome

Abstract The uremic syndrome is a complex clinical picture developing in the advanced stages of chronic kidney disease (CKD) resulting in a myriad of complications and a high early mortality. This picture is to a significant extent defined by retention of metabolites and peptides that with a preserved kidney function are excreted or degraded by the kidneys. In as far as those solutes have a negative biological/biochemical impact, they are called uremic toxins. Here, we describe the historical evolution of the scientific knowledge about uremic toxins and the role played in this process by the European Uremic Toxin Work Group (EUTox) during the last two decades. The earliest knowledge about a uremic toxin goes back to the early 17th century when the existence of what later would appear to be urea was recognized. It cost about two further centuries to better define the role of urea and its link to kidney failure and one more century to identify the relevance of post-translational modifications caused by urea such as carbamoylation. The knowledge progressively extended, especially from 1980 on, by the identification of more and more toxins and their adverse biological/biochemical impact. Progress of knowledge was paralleled and impacted by evolution of dialysis strategies. The last two decades, when Insights grew exponentially, coincides with the foundation and activity of EUTox. In the final section we summarize the role and accomplishments of EUTox and the part it is likely to play in future action, which should be organized around focus points like biomarker and potential target identification, intestinal generation, toxicity mechanisms and their correction, kidney and extracorporeal removal, patient-oriented outcomes, and toxin characteristics in acute kidney injury and transplantation.

scholarly journals Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1916
Author(s):  
Ziad Omran ◽  
Mahmood H. Dalhat ◽  
Omeima Abdullah ◽  
Mohammed Kaleem ◽  
Salman Hosawi ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Protein A ◽  
P53 Gene ◽  
Cancer Therapies ◽  
Transactivation Domain ◽  
P53 Family ◽  
Post Translational Modifications ◽  
P53 Status ◽  
Apoptotic Effects ◽  
High Degree

The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.

scholarly journals ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Sally Badawi ◽  
Bassam R. Ali
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
The Novel ◽  
Converting Enzyme ◽  
Post Translational Modifications ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Attachment ◽  
Novel Coronavirus ◽  
Effective Medication ◽  
Potential Use

AbstractWith the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

scholarly journals Tumor Suppressor SMAR1 Activates and Stabilizes p53 through Its Arginine-Serine-rich Motif

2005 ◽  
Vol 280 (16) ◽  
pp. 16019-16029 ◽  
Author(s):  
Archana Jalota ◽  
Kamini Singh ◽  
Lakshminarasimhan Pavithra ◽  
Ruchika Kaul-Ghanekar ◽  
Shahid Jameel ◽  
...  
Keyword(s):  
Cell Fate ◽  
The Novel ◽  
Nuclear Retention ◽  
Post Translational Modifications ◽  
Rich Domain ◽  
Dna Damaging Agents ◽  
Proliferation And Apoptosis ◽  
Interfering Rna ◽  
The Guardian

Various stresses and DNA-damaging agents trigger transcriptional activity of p53 by post-translational modifications, making it a global regulatory switch that controls cell proliferation and apoptosis. Earlier we have shown that the novel MAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal domain of SMAR1 (the arginine-serine-rich domain) that is phosphorylated by protein kinase C family proteins and is responsible for p53 interaction, activation, and stabilization within the nucleus. SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also demonstrate that this arginine-serine (RS)-rich domain triggers the various cell cycle modulating proteins that decide cell fate. Furthermore, phenotypic knock-down experiments using small interfering RNA showed that SMAR1 is required for activation and nuclear retention of p53. The level of phosphorylated p53 was significantly increased in the thymus of SMAR1 transgenic mice, showingin vivosignificance of SMAR1 expression. This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the “guardian of the genome.”

Wingless signaling in the Drosophila embryo: zygotic requirements and the role of the frizzled genes

Development ◽  
1999 ◽  
Vol 126 (3) ◽  
pp. 577-586 ◽  
Author(s):  
H. Muller ◽  
R. Samanta ◽  
E. Wieschaus
Keyword(s):  
Genomic Region ◽  
Drosophila Embryo ◽  
Surface Molecules ◽  
New Genes ◽  
Wingless Signaling ◽  
Frizzled Receptors ◽  
Signaling Receptors ◽  
Genomic Regions ◽  
High Degree

Wingless signaling plays a central role during epidermal patterning in Drosophila. We have analyzed zygotic requirements for Wingless signaling in the embryonic ectoderm by generating synthetic deficiencies that uncover more than 99% of the genome. We found no genes required for initial wingless expression, other than previously identified segmentation genes. In contrast, maintenance of wingless expression shows a high degree of zygotic transcriptional requirements. Besides known genes, we have identified at least two additional genomic regions containing new genes involved in Wingless maintenance. We also assayed for the zygotic requirements for Wingless response and found that no single genomic region was required for the cytoplasmic accumulation of Armadillo in the receiving cells. Surprisingly, embryos homozygously deleted for the candidate Wingless receptor, Dfrizzled2, showed a normal Wingless response. However, the Armadillo response to Wingless was strongly reduced in double mutants of both known members of the frizzled family in Drosophila, frizzled and Dfrizzled2. Based on their expression pattern during embryogenesis, different Frizzled receptors may play unique but overlapping roles in development. In particular, we suggest that Frizzled and Dfrizzled2 are both required for Wingless autoregulation, but might be dispensable for late Engrailed maintenance. While Wingless signaling in embryos mutant for frizzled and Dfrizzled2 is affected, Wingless protein is still internalized into cells adjacent to wingless-expressing cells. Incorporation of Wingless protein may therefore involve cell surface molecules in addition to the genetically defined signaling receptors of the frizzled family.

scholarly journals COVID-19 infection presenting with acute epiglottitis

2020 ◽  
Vol 2020 (9) ◽  
Author(s):  
Alexander Fondaw ◽  
Muzamil Arshad ◽  
Saba Batool ◽  
Brenton Robinson ◽  
Toral Patel
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Pediatric Population ◽  
Neural Tissue ◽  
Haemophilus Influenzae Type ◽  
Haemophilus Influenzae Type B ◽  
The Novel ◽  
Type B ◽  
Comorbid Conditions ◽  
Acute Epiglottitis ◽  
High Degree

Abstract In this case report, we present a novel presentation of acute epiglottitis in a patient with severe acute respiratory syndrome—coronavirus 2 (SARS-CoV-2) who presented to the emergency room in extremis and respiratory failure requiring emergent cricothyrotomy. Epiglottitis has become less common since the introduction and widespread use of the Haemophilus influenzae type B (Hib) vaccine. This reduction in cases has shifted demographics of the disease from the pediatric population towards adults with comorbid conditions. Interestingly there is a high degree of overlap between many of the comorbidities between epiglottitis and COVID-19. The novel severe acute respiratory syndrome—coronavirus 2 (SARS-CoV-2), also referred to as coronavirus disease 19 (COVID-19), has been reported to affect the gastrointestinal tract and neural tissue and has been implicated in necrotizing encephalitis. We report the first known case of the novel SARS-CoV-2 virus presenting with acute epiglottitis.

Neuroanatomical Profile of Antimaniac Effects of Histone Deacetylases Inhibitors

2011 ◽  
Vol 43 (3) ◽  
pp. 207-214 ◽  
Author(s):  
Camila O. Arent ◽  
Samira S. Valvassori ◽  
Gabriel R. Fries ◽  
Laura Stertz ◽  
Camila L. Ferreira ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Histone Deacetylases Inhibitors
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