Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway

2014 ◽  
Vol 57 (3) ◽  
pp. 567-577 ◽  
Author(s):  
Chunlin Zhuang ◽  
Zhenyuan Miao ◽  
Yuelin Wu ◽  
Zizhao Guo ◽  
Jin Li ◽  
...  
Keyword(s):  
Small Molecules ◽  
Cancer Therapeutics ◽  
Orally Active

scholarly journals RecQ helicases in DNA repair and cancer targets

2020 ◽  
Vol 64 (5) ◽  
pp. 819-830
Author(s):  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Dna Repair ◽  
Small Molecules ◽  
Atp Hydrolysis ◽  
Cancer Therapeutics ◽  
Genome Integrity ◽  
Mechanistic Study ◽  
Synthetic Lethal ◽  
Recq Helicases ◽  
Repair Pathways ◽  
Higher Eukaryotes

Abstract Helicases are enzymes that use the energy derived from ATP hydrolysis to catalyze the unwinding of DNA or RNA. The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is now considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. In this review, we summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. Finally, we consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics.

Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials

2020 ◽  
Vol 20 (6) ◽  
pp. 433-457 ◽  
Author(s):  
Nicola Relitti ◽  
Akella P. Saraswati ◽  
Stefano Federico ◽  
Tuhina Khan ◽  
Margherita Brindisi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Tandem Repeats ◽  
Cancer Therapeutics ◽  
High Specificity ◽  
Telomerase Activity ◽  
Current Status ◽  
Anti Cancer ◽  
Therapeutic Tools ◽  
Made In

Telomeres are protective chromosomal ends that shield the chromosomes from DNA damage, exonucleolytic degradation, recombination, and end-to-end fusion. Telomerase is a ribonucleoprotein that adds TTAGGG tandem repeats to the telomeric ends. It has been observed that 85 to 90% of human tumors express high levels of telomerase, playing a crucial role in the development of cancers. Interestingly, the telomerase activity is generally absent in normal somatic cells. This selective telomerase expression has driven scientists to develop novel anti-cancer therapeutics with high specificity and potency. Several advancements have been made in this area, which is reflected by the enormous success of the anticancer agent Imetelstat. Since the discovery of Imetelstat, several research groups have contributed to enrich the therapeutic arsenal against cancer. Such contributions include the application of new classes of small molecules, peptides, and hTERT-based immunotherapeutic agents (p540, GV1001, GRNVAC1 or combinations of these such as Vx-001). Many of these therapeutic tools are under different stages of clinical trials and have shown promising outcomes. In this review, we highlight the current status of telomerase-based cancer therapeutics and the outcome of these investigations.

scholarly journals New Small Molecule Drugs for Thrombocytopenia: Chemical, Pharmacological, and Therapeutic Use Considerations

2019 ◽  
Vol 20 (12) ◽  
pp. 3013 ◽  
Author(s):  
Page Clemons Bankston ◽  
Rami A. Al-Horani
Keyword(s):  
Small Molecules ◽  
Previous Treatment ◽  
Specific Patient ◽  
Chemical Structures ◽  
Small Molecule Drugs ◽  
Thrombopoietin Receptor ◽  
Insufficient Response ◽  
Syk Inhibitor ◽  
New Treatments ◽  
Orally Active

This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.

The Potential Targets and Mechanisms of a Carbazole and Pyrazole Containing Anticancer Compound

2020 ◽  
Vol 20 (5) ◽  
pp. 364-371
Author(s):  
Jingping Xie ◽  
John C. Gore
Keyword(s):  
Small Molecules ◽  
Real Time ◽  
Cell Lines ◽  
Real Time Pcr ◽  
Expression Profiling ◽  
Cancer Therapeutics ◽  
Computer Assisted ◽  
Motif Analysis ◽  
Selection Operator ◽  
Anticancer Compound

Aims: Characterization of a small anticancer compound. Background: The development of small molecules as new anti-cancer therapeutics is necessary to improve anti-tumor efficacy and reduce toxicities, especially for the treatment of brain tumors, where only small molecules can effectively cross the brain-blood barrier. Several novel hits were previously selected by concurrently screening colon and glioma cancer cell lines with a sensorconjugated reporter system. Here, we focused on one of them. Objective: Elucidating the potential target(s) of a novel anticancer compound. Methods: Computer-assisted structural and motif analysis (least absolute shrinkage and selection operator or LASSO score) was used to assess compound’s targets, then direct kinase activity assays were used for the confirmation; Western blot of phosphorylated kinases, as well as FACS and caspase 3/7 activity assays, were used to decipher the action mechanisms. Finally, the expression profiling of proteins involved in various G-protein pathways by real-time PCR was performed. Result: The small chemical, (4E)-4-[2-(9-ethyl-9H-carbazol-3-yl)hydrazin-1-ylidene]-3-methyl- 4,5-dihydro-1H-pyrazol-5-one, with a formula C18H17N5O and MW of 319.36, designated as VUGX01, was predicted to be a ligand/inhibitor to receptor tyrosine kinases (RTKs) by computer analysis (least absolute shrinkage and selection operator or LASSO score). However, direct analysis with recombinant kinases showed that it is not an effective inhibitor to the popular receptor kinases at 1μM concentration. This compound can activate caspases in some tumor cell lines but has minimal effects on the cell cycle. Drug treatments lead to the changes in phosphorylation of AKT and c- RAF, as well as the expression level of MAP2K, suggesting this compound may interact with Gprotein coupled receptors (GPCRs). The expression profiling of 82 proteins involved in various Gprotein pathways by real-time PCR showed that the treatment up-regulates the expression of several proteins, including angiotensinogen, angiotensin II receptor, and IP3-kinase catalytic subunit gamma. Conclusion: VUGX01 can effectively block proliferation and induce apoptosis of certain types of cancer cells, even it is predicted by high LASSO score, but it is not an effective RTKs inhibitor, it may inhibit cell growth through acting as a novel ligand to one or several GPCRs.

scholarly journals Small Molecules Targeting c-Myc Oncogene: Promising Anti-Cancer Therapeutics

2014 ◽  
Vol 10 (10) ◽  
pp. 1084-1096 ◽  
Author(s):  
Bing-Jia Chen ◽  
Yan-Ling Wu ◽  
Yoshimasa Tanaka ◽  
Wen Zhang
Keyword(s):  
Small Molecules ◽  
Cancer Therapeutics ◽  
Myc Oncogene ◽  
Anti Cancer

scholarly journals Partitioning of cancer therapeutics in nuclear condensates

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1386-1392 ◽  
Author(s):  
Isaac A. Klein ◽  
Ann Boija ◽  
Lena K. Afeyan ◽  
Susana Wilson Hawken ◽  
Mengyang Fan ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Small Molecules ◽  
Tumor Cells ◽  
Drug Target ◽  
Cancer Therapeutics ◽  
Specific Protein ◽  
Antineoplastic Drugs ◽  
Disease Therapy ◽  
Drug Partitioning

The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

scholarly journals G-Quadruplex targeting ligands: A hope and a new horizon in Cancer Therapeutics

2018 ◽  
Author(s):  
Nilanjan Banerjee ◽  
Suman Panda ◽  
Subhrangsu Chatterjee
Keyword(s):  
Secondary Structure ◽  
Cancer Treatment ◽  
Small Molecules ◽  
Human Genome ◽  
Cancer Therapeutics ◽  
Structural Diversity ◽  
Quadruplex Structure ◽  
G Quadruplex ◽  
Therapeutic Research ◽  
Widespread Interest

G-quadruplex, a unique secondary structure in nucleic acids found throughout human genome elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, G-quadruplex structure regulates transcription, translation, splicing, telomere stability etc. Changes in its structure and stability lead to differential expression of oncogenes causing cancer. Thus, targeting G-Quadruplex structures with small molecules/ other biologics has shown elevated research interest. Covering previous reports, in this review we try to enlighten the facts on the structural diversity in G-quadruplex ligands aiming to provide newer insights to design first-in-class drugs for the next generation cancer treatment.

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