scholarly journals Small Molecules Targeting Biological Clock; A Novel Prospective for Anti-Cancer Drugs

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4937
Author(s):  
Sadia Rahman ◽  
Karlo Wittine ◽  
Mirela Sedić ◽  
Elitza P. Markova-Car
Keyword(s):  
Circadian Rhythm ◽  
Small Molecules ◽  
Small Molecule ◽  
Environmental Conditions ◽  
Recent Progress ◽  
Biological Clock ◽  
New Drugs ◽  
Anti Cancer ◽  
Growing Body ◽  
Potential Use

The circadian rhythms are an intrinsic timekeeping system that regulates numerous physiological, biochemical, and behavioral processes at intervals of approximately 24 h. By regulating such processes, the circadian rhythm allows organisms to anticipate and adapt to continuously changing environmental conditions. A growing body of evidence shows that disruptions to the circadian rhythm can lead to various disorders, including cancer. Recently, crucial knowledge has arisen regarding the essential features that underlie the overt circadian rhythm and its influence on physiological outputs. This knowledge suggests that specific small molecules can be utilized to control the circadian rhythm. It has been discovered that these small molecules can regulate circadian-clock-related disorders such as metabolic, cardiovascular, inflammatory, as well as cancer. This review examines the potential use of small molecules for developing new drugs, with emphasis placed on recent progress that has been made regarding the identification of small-molecule clock modulators and their potential use in treating cancer.

scholarly journals Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

2019 ◽  
Vol 20 (16) ◽  
pp. 4017 ◽  
Author(s):  
Kaalak Reddy ◽  
Jana R. Jenquin ◽  
John D. Cleary ◽  
J. Andrew Berglund
Keyword(s):  
Small Molecules ◽  
Myotonic Dystrophy ◽  
Small Molecule ◽  
Disease Onset ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type ◽  
Rna Toxicity ◽  
Complex Mechanisms ◽  
Potential Use

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).

scholarly journals Cyanine dye mediated mitochondrial targeting enhances the anti-cancer activity of small-molecule cargoes

2020 ◽  
Vol 56 (34) ◽  
pp. 4672-4675 ◽  
Author(s):  
Alexander R. Nödling ◽  
Emily M. Mills ◽  
Xuefei Li ◽  
Davide Cardella ◽  
Edward J. Sayers ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Cyanine Dye ◽  
Mitochondrial Targeting ◽  
Anti Cancer ◽  
Cancer Activity

Conjugation of small molecules to a simple cyanine dye can lead to organelle-specific delivery.

Sensing the impact of environment on small molecule differentiation of RNA sequences

2017 ◽  
Vol 53 (100) ◽  
pp. 13363-13366 ◽  
Author(s):  
Christopher S. Eubanks ◽  
Amanda E. Hargrove
Keyword(s):  
Pattern Recognition ◽  
Small Molecules ◽  
Small Molecule ◽  
Environmental Conditions ◽  
Rna Structures ◽  
Rna Sequences ◽  
The Impact

Pattern recognition of RNA with small molecules (PRRSM) reveals the impact of environmental conditions on the differentiation of RNA structures.

scholarly journals Small molecule inhibitors of the mitochondrial ClpXP protease possess cytostatic potential and re-sensitize chemo-resistant cancers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Martina Meßner ◽  
Melanie M. Mandl ◽  
Mathias W. Hackl ◽  
Till Reinhardt ◽  
Maximilian A. Ardelt ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Breast Cancer Cell Lines ◽  
Cancer Therapies ◽  
Oxygen Species ◽  
Transport Chain ◽  
Anti Cancer ◽  
Major Attention

AbstractThe human mitochondrial ClpXP protease complex (HsClpXP) has recently attracted major attention as a target for novel anti-cancer therapies. Despite its important role in disease progression, the cellular role of HsClpXP is poorly characterized and only few small molecule inhibitors have been reported. Herein, we screened previously established S. aureus ClpXP inhibitors against the related human protease complex and identified potent small molecules against human ClpXP. The hit compounds showed anti-cancer activity in a panoply of leukemia, liver and breast cancer cell lines. We found that the bacterial ClpXP inhibitor 334 impairs the electron transport chain (ETC), enhances the production of mitochondrial reactive oxygen species (mtROS) and thereby promotes protein carbonylation, aberrant proteostasis and apoptosis. In addition, 334 induces cell death in re-isolated patient-derived xenograft (PDX) leukemia cells, potentiates the effect of DNA-damaging cytostatics and re-sensitizes resistant cancers to chemotherapy in non-apoptotic doses.

scholarly journals AnnapuRNA: a scoring function for predicting RNA-small molecule interactions

2020 ◽  
Author(s):  
Filip Stefaniak ◽  
Janusz M. Bujnicki
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Computer Aided Design ◽  
Structure Prediction ◽  
Scoring Function ◽  
Computational Method ◽  
New Drugs ◽  
Scoring Functions ◽  
Ligand Complex ◽  
Molecule Interactions

AbstractRNA is considered as an attractive target for new small molecule drugs. Designing active compounds can be facilitated by computational modeling. Most of the available tools developed for these prediction purposes, such as molecular docking or scoring functions, are parametrized for protein targets. The performance of these methods, when applied to RNA-ligand systems, is insufficient. To overcome these problems, we developed AnnapuRNA, a new knowledge-based scoring function designed to evaluate RNA-ligand complex structures, generated by any computational docking method. We also evaluated three main factors that may influence the structure prediction, i.e., starting conformer of a ligand, the docking program, and the scoring function used. We applied the AnnapuRNA method for a post-hoc study of the recently published structures of the FMN riboswitch. Software is available at https://github.com/filipspl/AnnapuRNAAuthor SummaryDrug development is a lengthy and complicated process, which requires costly experiments on a very large number of chemical compounds. The identification of chemical molecules with desired properties can be facilitated by computational methods. A number of methods were developed for computer-aided design of drugs that target protein molecules. However, recently the ribonucleic acid (RNA) emerged as an attractive target for the development of new drugs. Unfortunately, the portfolio of the computer methods that can be applied to study RNA and its interactions with small chemical molecules is very limited. This situation motivated us to develop a new computational method, with which to predict RNA-small molecule interactions. To this end, we collected the information on the statistics of interactions in experimentally determined structures of complexes formed by RNA with small molecules. We then used the statistical data to train machine learning methods aiming to distinguish between RNA-ligand interactions observed experimentally and other interactions that can be observed in theoretical analyses, but are not observed in nature. The resulting method called AnnapuRNA is superior to other similar tools and can be used to predict preferred ligands of RNA molecules and how RNA and small molecules interact with each other.

scholarly journals Inhibition of p53 inhibitors: progress, challenges and perspectives

2019 ◽  
Vol 11 (7) ◽  
pp. 586-599 ◽  
Author(s):  
Gema Sanz ◽  
Madhurendra Singh ◽  
Sylvain Peuget ◽  
Galina Selivanova
Keyword(s):  
Tumor Suppressor ◽  
Small Molecules ◽  
Recent Progress ◽  
Strong Support ◽  
Tumor Suppressor Function ◽  
Wild Type ◽  
Negative Regulators ◽  
Anti Cancer ◽  
P53 Reactivation ◽  
Different Origin

Abstract p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.

Oxazole-Based Compounds As Anticancer Agents

2020 ◽  
Vol 26 (41) ◽  
pp. 7337-7371 ◽  
Author(s):  
Maria A. Chiacchio ◽  
Giuseppe Lanza ◽  
Ugo Chiacchio ◽  
Salvatore V. Giofrè ◽  
Roberto Romeo ◽  
...  
Keyword(s):  
Cancer Research ◽  
Drug Discovery ◽  
Anticancer Agents ◽  
Heterocyclic Compounds ◽  
Chemical Diversity ◽  
Biologically Active ◽  
New Drugs ◽  
The Core ◽  
Anti Cancer ◽  
Biologically Active Derivatives

: Heterocyclic compounds represent a significant target for anti-cancer research and drug discovery, due to their structural and chemical diversity. Oxazoles, with oxygen and nitrogen atoms present in the core structure, enable various types of interactions with different enzymes and receptors, favoring the discovery of new drugs. Aim of this review is to describe the most recent reports on the use of oxazole-based compounds in anticancer research, with reference to the newly discovered iso/oxazole-based drugs, to their synthesis and to the evaluation of the most biologically active derivatives. The corresponding dehydrogenated derivatives, i.e. iso/oxazolines and iso/oxazolidines, are also reported.

The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review

2019 ◽  
Vol 19 (18) ◽  
pp. 1650-1675 ◽  
Author(s):  
Damoder Reddy Motati ◽  
Dilipkumar Uredi ◽  
E. Blake Watkins
Keyword(s):  
Small Molecule ◽  
Viral Entry ◽  
Biological Evaluation ◽  
New Drugs ◽  
Design Synthesis ◽  
Mortality And Morbidity ◽  
Glycoprotein Gp120 ◽  
Hiv Entry ◽  
Immunodeficiency Syndrome ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.

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